Solubilized topoisomerase poisons

ABSTRACT

The invention provides compounds of formula I: 
                         
wherein
         A, B, W, Y, Z, and R 1  have any of the meanings defined in the specification and their pharmaceutically acceptable salts. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I, and therapeutic methods for treating cancer using compounds of formula I.

RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. 111(a) of Ser. No.11/210,456, filed on Aug. 24, 2005, which is a continuation of Ser. No.10/846,834, filed May 14, 2004, which is U.S. Pat. No. 7,049,315, whichis a continuation of PCT/US02/36901, filed Nov. 14, 2002 and publishedin English on May 22, 2003 as WO 03/041660 A2, which claimed priorityunder 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/332,734,filed Nov. 14, 2001, which applications and publications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

DNA-topoisomerases are enzymes which are present in the nuclei of cellswhere they catalyze the breaking and rejoining of DNA strands, whichcontrol the topological state of DNA. Recent studies also suggest thattopoisomerases are also involved in regulating template supercoilingduring RNA transcription. There are two major classes of mammaliantopoisomerases. DNA-topoisomerase-I catalyzes changes in the topologicalstate of duplex DNA by performing transient single-strand breakage-unioncycles. In contrast, mammalian topoisomerase II alters the topology ofDNA by causing a transient enzyme bridged double-strand break, followedby strand passing and resealing. Mammalian topoisomerase II has beenfurther classified as Type II α and Type II β. The antitumor activityassociated with agents which are topoisomerase poisons is associatedwith their ability to stabilize the enzyme-DNA cleavable complex. Thisdrug-induced stabilization of the enzyme-DNA cleavable complexeffectively converts the enzyme into a cellular poison.

Several antitumor agents in clinical use have potent activity asmammalian topoisomerase II poisons. These include adriamycin,actinomycin D, daunomycin, VP-16, and VM-26 (teniposide orepipodophyllotoxin). In contrast to the number of clinical andexperimental drugs which act as topoisomerase II poisons, there arecurrently only a limited number of agents which have been identified astopoisomerase I poisons. Camptothecin and its structurally-relatedanalogs are among the most extensively studied topoisomerase I poisons.Recently, bi- and terbenzimidazoles (Chen et al., Cancer Res. 1993, 53,1332-1335; Sun et al., J. Med. Chem. 1995, 38, 3638-3644; Kim et al., J.Med. Chem. 1996, 39, 992-998), certain benzo[c]phenanthridine andprotoberberine alkaloids and their synthetic analogs (Makhey et al.,Med. Chem. Res. 1995, 5, 1-12; Janin et al., J. Med. Chem. 1975, 18,708-713; Makhey et al., Bioorg. & Med. Chem. 1996, 4, 781-791), as wellas the fungal metabolites, bulgarein (Fujii et al., J. Biol. Chem. 1993,268, 13160-13165) and saintopin (Yamashita et al., Biochemistry 1991,30, 5838-5845) and indolocarbazoles (Yamashita et al., Biochemistry1992, 31, 12069-12075) have been identified as topoisomerase I poisons.Other topoisomerase poisons have been identified including certainbenzo[i]phenanthridine and cinnoline compounds (see LaVoie et al., U.S.Pat. No. 6,140,328 (735.037WO1), and WO 01/32631(735.044WO1)). Whilethese compounds are useful they are somewhat limited due to lowsolubility.

SUMMARY OF THE INVENTION

Applicant has discovered compounds with improved solubility propertieswhich also have inhibitory activity against topoisomerase I and/ortopoisomerase II. Accordingly, the invention provides a compound of theinvention which is a compound of formula I:

wherein:

A and B are independently N or CH;

W is N or CH;

R₃ and R₄ are each independently H, (C₁-C₆)alkyl, or substituted(C₁-C₆)alkyl, or R₃ and R₄ together are ═O, ═S, ═NH or ═N—R₂;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆) alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ is a —(C₁-C₆)alkyl substituted with one or more solubilizing groupsR_(z);

R₂ is (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl; and

R_(c) and R_(d) are each independently (C₁-C₆) alkyl or substituted(C₁-C₆) alkyl; or R_(c) and R_(d) together with the nitrogen to whichthey are attached form a N′-{(C₁-C₆)alkyl}piperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising aeffective amount of a compound of the invention in combination with apharmaceutically acceptable diluent or carrier.

The invention also provides a method for modulating topoisomeraseactivity in a mammal in need of such treatment comprising administeringto the mammal an amount of a compound of the invention effective toprovide a topoisomerase modulating effect.

The invention also provides a method of inhibiting cancer cell growth,comprising administering to a mammal afflicted with cancer, an amount ofa compound of the invention, effective to inhibit the growth of saidcancer cells.

The invention also provides a method comprising inhibiting cancer cellgrowth by contacting said cancer cell in vitro or in vivo with an amountof a compound of the invention, effective to inhibit the growth of saidcancer cell.

The invention also provides a compound of the invention for use inmedical therapy, preferably for use in treating cancer, for example,solid tumors, as well as the use of a compound of the invention for themanufacture of a medicament useful for the treatment of cancer, forexample, solid tumors.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of formula I are useful to prepare other compounds offormula I.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described.

“(C₁-C₆)alkyl” denotes both straight and branched carbon chains with oneor more, for example, 1, 2, 3, 4, 5, or 6, carbon atoms, but referenceto an individual radical such as “propyl” embraces only the straightchain radical, a branched chain isomer such as “isopropyl” beingspecifically referred to.

“Substituted (C₁-C₆)alkyl” is an alkyl group of the formula (C₁-C₆)alkylas defined above wherein one or more (e.g. 1 or 2) carbon atoms in thealkyl chain have been replaced with a heteroatom independently selectedfrom —O—, —S— and NR— (where R is hydrogen or C₁-C₆alkyl) and/or whereinthe alkyl group is substituted with from 1 to 5 substituentsindependently selected from cycloalkyl, substituted cycloalkyl,(C₁-C₆)alkoxycarbonyl (e.g. —CO₂Me), cyano, halo, hydroxy, oxo (═O),carboxy (COOH), aryloxy, heteroaryloxy, heterocyclooxy, nitro, and—NR_(a)R_(b), wherein R_(a) and R_(b) may be the same or different andare chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl,heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryland heterocyclic. Substituted (C₁-C₆)alkyl groups are exemplified by,for example, groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl,2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl,2-carboxyethyl, hydroxylated alkyl amines, such as 2-hydroxyaminoethyl,and like groups. Preferred substituted (C₁-C₆)alkyl groups are(C₁-C₆)alkyl groups substituted with one or more substituents of theformula-NR_(a)R_(b) where R_(a) and R_(b) together with the nitrogen towhich they are attached form of nitrogen containing heterocyclic ring.Specific examples of such heterocyclic rings include piperazino,pyrrolidino, piperidino, morpholino, or thiomorpholino. Other preferredsubstituted (C₁-C₆)alkyl groups are (C₁-C₆)alkyl groups substituted withone or more carbon-linked oxygen containing heterocyclic rings. Specificexamples of such oxygenated heterocyclic rings are, for example,tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, and like groups.

“(C₁-C₆)alkoxy” refers to groups of the formula (C₁-C₆)alkyl-O—, where(C₁-C₆)alkyl is as defined herein. Preferred alkoxy groups include, byway of example, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, andlike groups.

“Substituted (C₁-C₆)alkoxy” refers to a substituted (C₁-C₆)alkyl-O—group wherein substituted (C₁-C₆)alkyl is as defined above. Substituted(C₁-C₆)alkoxy is exemplified by groups such as O—CH₂CH₂—NR_(a)R_(b),O—CH₂CH₂—CHR_(a)R_(b), or O—CH₂—CHOH—CH₂—OH, and like groups. Preferredsubstituted (C₁-C₆)alkoxy groups are (C₁-C₆)alkyl substituted with oneor more substituents of the formula-NR_(a)R_(b) where R_(a) and R_(b)together with the nitrogen to which they are attached form of aheterocyclic ring. Specific examples of such heterocyclic rings includepiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino.Other preferred substituted (C₁-C₆)alkoxy groups are (C₁-C₆)alkoxygroups substituted with one or more carbon-linked oxygen containingheterocyclic rings. Specific examples of preferred oxygenatedheterocyclic ring substituents are, for example, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups. Specific examples ofsuch oxygenated heterocyclic rings are, for example, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups.

“(C₁-C₆)alkanoyloxy” includes, by way of example, formyloxy, acetoxy,propanoyloxy, iso-propanoyloxy, n-butanoyloxy, tert-butanoyloxy,sec-butanoyloxy, n-pentanoyloxy, n-hexanoyloxy, 1,2-dimethylbutanoyloxy,and like groups.

“Substituted (C₁-C₆)alkanoyloxy” refers to a (C₁-C₆)alkanoyloxy groupwherein one or more (e.g. 1 or 2) carbon atoms in the alkyl chain havebeen replaced with a heteroatom independently selected from —O—, —S— andNR— (where R is hydrogen or C₁-C₆alkyl) and/or wherein the alkyl groupis substituted with from 1 to 5 substituents independently selected fromcycloalkyl, substituted cycloalkyl, (C₁-C₆)alkoxycarbonyl (e.g. —CO₂Me),cyano, halo, hydroxy, oxo (═O), carboxy (COOH), aryloxy, heteroaryloxy,heterocyclooxy, nitro, and —NR_(a)R_(b), wherein R_(a) and R_(b) may bethe same or different and are chosen from hydrogen, alkyl, arylalkyl,heteroarylalkyl, heterocycloalkyl, cycloalkyl, substituted cycloalkyl,aryl, heteroaryl and heterocyclic. Substituted (C₁-C₆)alkanoyloxy isexemplified by groups such as —O—C(═O)CH₂—NR_(a)R_(b), andO—C(═O)—CHOH—CH₂—OH. Preferred substituted (C₁-C₆)alkanoyloxy groups aregroups wherein the alkyl group is substituted with one or more nitrogenand oxygen containing heterocyclic rings such as piperazino,pyrrolidino, piperidino, morpholino, thiomorpholino, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups.

Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic. Examples of aryl include phenyl, indenyl, and naphthyl.

Heteroaryl encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absentor is H, O, (C₁-C₄)alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.Examples of heteroaryl include furyl, imidazolyl, triazolyl, triazinyl,oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl,pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl(or its N-oxide), indolyl, isoquinolyl (or its N-oxide) and quinolyl (orits N-oxide).

The term “heterocycle” refers to a monovalent saturated or partiallyunsaturated cyclic non-aromatic group which contains at least oneheteroatom, preferably 1 to 4 heteroatoms, selected from nitrogen(NR_(x), wherein R_(x) is hydrogen, alkyl, or a direct bond at the pointof attachment of the heterocycle group), sulfur, phosphorus, and oxygenwithin at least one cyclic ring and which may be monocyclic ormulti-cyclic. Such heterocycle groups preferably contain from 3 to 10atoms. The point of attachment of the heterocycle group may be a carbonor nitrogen atom. This term also includes heterocycle groups fused to anaryl or heteroaryl group, provided the point of attachment is on anon-aromatic heteroatom-containing ring. Representative heterocyclegroups include, by way of example, pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl,1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl and the like.

“Aryloxy” refers to a group of the formula aryl-O—, where aryl is asdefined herein. Examples of aryloxy groups include, phenoxy and1-naphthyloxy.

“Heteroaryloxy” refers to a group of the formula heteroaryl-O—, whereheteroaryl is as defined herein. Examples of heteroaryloxy groupsinclude, 3-piperidyloxy, 3-furyloxy, and 4-imidazoyloxy.

“Heterocyclooxy” refers to a group of the formula heterocycle-O—, whereheterocycle is as defined herein. Examples of heterocyclooxy groupsinclude, 4-morpholinooxy and 3-tetrahydrofuranyloxy.

“Arylalkyl” refers to a group of the formula aryl-(C₁-C₆)alkyl-, wherearyl and (C₁-C₆)alkyl are as defined herein.

“Heteroarylalkyl” refers to a group of the formulaheteroaryl-(C₁-C₆)alkyl-, where heteroaryl and (C₁-C₆)alkyl are asdefined herein.

“Heterocycloalkyl” refers to a group of the formulaheterocycle-(C₁-C₆)alkyl-, where heterocycle and (C₁-C₆)alkyl are asdefined herein.

“Solubilizing group(s) R_(z)” is a substituent that increases the watersolubility of the compound of formula I compared to the correspondingcompound lacking the R substituent. Examples of solubilizing groupsinclude substituents independently selected from substituted(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl (e.g. —CO₂Me), cyano, halo, hydroxy,oxo (═O), carboxy (COOH), aryloxy, heteroaryloxy, heterocyclooxy, nitro,and —NR_(a)R_(b), wherein R_(a) and R_(b) may be the same or differentand are chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl,heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryland heterocyclic.

Preferred R₁ groups are exemplified by, for example, groups such ashydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl,2-methylaminoethyl, 3-dimethylaminopropyl, 2-carboxyethyl, hydroxylatedalkyl amines, such as 2-hydroxyaminoethyl, and like groups. Otherpreferred R₁ groups are (C₁-C₆)alkyl groups substituted with one or moresubstituents of the formula —NR_(a)R_(b) where R_(a) and R_(b) togetherwith the nitrogen to which they are attached form a nitrogen containingheterocyclic ring, or (C₁-C₆)alkyl groups substituted with one or moreoxygen containing heterocyclic rings. Specific examples of suchheterocyclic rings include piperazino, pyrrolidino, piperidino,morpholino, or thiomorpholino. Still other preferred R₁ groups are(C₁-C₆)alkyl groups substituted with one or more carbon-linked oxygencontaining heterocyclic rings. Specific examples of such oxygenatedheterocyclic rings are, for example, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy.

A specific value for A is CH.

Another specific value for A is N.

A specific value for B is N.

Another specific value for B is CH.

A specific value for W is N.

Another specific value for W is CH.

A specific value for Y is OH.

Another specific value for Y is (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₃.

Another specific value for Y is substituted (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₂CH₂OH.

Another specific value for Y is —OCH₂CH₂OCH₂CH₃.

Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Y is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for Z is OH.

Another specific value for Z is (C₁-C₆)alkoxy.

Another specific value for Z is OCH₃.

Another specific value for Z is substituted (C₁-C₆)alkoxy.

Another specific value for Z is —OCH₂CH₂OH.

Another specific value for Z is —OCH₂CH₂OCH₂CH₃.

Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Z is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for R₃ and R₄ is H.

Another specific value for R₃ and R₄ together is ═O.

Another specific value for R₃ and R₄ together is ═S.

Another specific value for R₃ and R₄ together is ═NH.

Another specific value for R₃ and R₄ together is ═N—R₂ Another specificvalue for R₃ and R₄ together is ═N—R₂ where R₂ is (C₁-C₆)alkyl.

Another specific value for R₃ and R₄ together is ═N—R₂ where R₂ issubstituted (C₁-C₆)alkyl.

Another specific value for R₃ is H and R₄ is (C₁-C₆)alkyl.

Another specific value for R₃ is H and R₄ is substituted (C₁-C₆)alkyl.

Another specific value for R₃ is (C₁-C₆)alkyl and R₄ is substituted(C₁-C₆)alkyl.

Another specific value for R₃ and R₄ is substituted (C₁-C₆)alkyl

A specific value for R₁ is 2-hydroxyethyl.

Another specific value for R₁ is 2-aminoethyl.

Another specific value for R₁ is 2-(N,N′-dimethylamino)ethyl.

Another specific value for R₁ is 2-(N,N′-diethylamino)ethyl.

Another specific value for R₁ is 2-(N,N′-diethanolamino)ethyl of theformula —CH₂—CH₂—N(—CH₂—CH₂—OH)₂.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more hydroxy, mercapto, carboxy, amino, piperazinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl with from 2 to 4carbon atoms and substituted with one to two groups selected fromhydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or 1,4-dioxanyl.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

A preferred compound of formula (I) is the compound11,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-11-[2-(dimethylamino)ethyl]-5,6,11-triazachrysen-12-one,or a pharmaceutically acceptable salt thereof.

A specific compound of formula I is a compound of formula II:

Another specific compound of formula I is a compound of formula III:

Another specific compound of formula I is a compound of formula IV:

Another specific compound of formula I is a compound of formula V:

A specific compound of formula I is a compound of formula VI:

Another specific compound of formula I is a compound of formula VII:

Another specific compound of formula I is a compound of formula VIII:

Another specific compound of formula I is a compound of formula IX:

Another specific compound of formula I is any of the above compounds offormulas II-IX as their pharmaceutically acceptable salts.

Certain compounds of formula (I) can function as prodrugs for othercompounds of formula (I). For example, a compound of formula (I) whereinY and/or Z is —O—P(═O)(OH)₂, or —C(═O)NR_(c)R_(d); can function as aprodrug for a corresponding compound of formula (I) wherein Y and or Zis hydroxy. Accordingly, a specific sub set of compounds of formula (I)are compounds wherein Y and/or Z is —O—P(═O)(OH)₂, or—O—C(═O)NR_(c)R_(d). A particularly preferred compound is a compound offormula (I) wherein Y and/or Z is —O—P(═O)(OH)₂. Another preferredcompound is a compound of formula (I) wherein Y and/or Z is—O—C(═O)NR_(e)R_(d), wherein R_(e) and/or R_(d) is (C₁-C₆)alkylsubstituted with one or more —NR_(e)R_(f) wherein R_(e) and R_(f) areeach independently (C₁-C₆)alkyl. Another preferred compound is acompound of formula (I) wherein Y and/or Z is —O—C(═O)NR_(e)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-{(C₁-C₆)alkyl}piperazino, pyrrolidino, or piperidinoring. A more preferred compound is a compound of formula (I) wherein Yand/or Z is —O—C(═O)NR_(c)R_(d), wherein R_(e) and R_(d) together withthe nitrogen to which they are attached form a piperidino ring, whichring is optionally substituted with an N-linked heterocycle (e.g.piperidino) ring.

The present invention provides compounds and intermediate compounds offormula I and a method of making compounds of formula I and intermediatecompounds of formula I wherein R₁ is —CH₂—OH and like 1-hydroxysubstituted (C₁-C₆)alkyl groups, or the corresponding alkanoyloxy ester,phosphoric acid ester, or phosphate ester comprising reacting thecompound of formula I where R₁ is H with a suitable hydroxy producingcompound, for example a carbonyl compound, such as an aldehyde, to forma compound where R₁ is —CH₂—OH or like 1-hydroxy substituted(C₁-C₆)alkyl groups. The corresponding alkanoyloxy ester, phosphoricacid ester or phosphate ester compounds can be prepared by reacting theresulting compound where R₁ is —CH₂—OH or like 1-hydroxy substituted(C₁-C₆)alkyl groups with a suitable ester forming reagent, such as anacyl halide, phosphoric acid ester, or phosphoryl halide compound. Theabove intermediate compounds can also function as prodrugs for othercompounds of formula (I). It is understood by one skilled in the artthat the groups here R₁ is —CH₂—OH or like 1-hydroxy substituted(C₁-C₆)alkyl groups can be stabilized or preserved with known protectinggroups, such as carboxylate esters, phosphates, and like groups. See forexample, Krogsgaard-Larsen P and Bundgaard A (eds), “A Textbook Of DrugDesign and Development,” 2nd ed., Harwood, 1996.

A compound of formula I can be prepared by subjecting a correspondingintermediate of formula A to suitable cyclization conditions; forexample, by treatment with palladium acetate and triphenyl phosphine, asillustrated in Scheme 1 below. A compound of formula I can also beprepared by subjecting a corresponding intermediate of formula B toconditions suitable for the formation of the tetracyclic ring system;for example by treatment with a suitable tin reagent, as illustrated inScheme 2 below. Compounds of the present invention include intermediatesof formulas A and B.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons, 4thed., 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W. A.Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2nd ed., 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures that are known in the art, or can beprepared using procedures illustrated below.

Chlorination of Compound 1 yields chloro-compound 2, which can beconverted to the corresponding amine by formation of the correspondingphenoxy intermediate and subsequent reaction with an appropriate amine.The resulting amine can be acylated with the appropriately substitutedacylchloride to provide the intermediate of formula A.

Similarly, an intermediate of formula B can be prepared from readilyavailable starting materials using procedures that are known in the art,or can be prepared using procedures illustrated below.

Bromination of compound 1 provides compound 3, which can be converted tohalo-compound 4 using procedures known in the art. Reaction with asuitable amine or ammonium salt provides amino compound 5, which can beconverted to an intermediate of formula B by treatment with a suitableacid chloride 6.

An alternative route to the formation of 5,6-dihydro derivatives offormula I involves either reduction of the lactam or desulfurization ofthe thioamide as illustrated by the following. Additionally, one canmodify compounds of formula I to provide other related compounds offormula I as illustrated below.

The starting materials employed in the synthetic methods describedherein are commercially available, have been reported in the scientificliterature, or can be prepared from readily available starting materialsusing procedures known in the field. It may be desirable to optionallyuse a protecting group during all or portions of the above describedsynthetic procedures. Such protecting groups and methods for theirintroduction and removal are well known in the art. See Greene, T. W.;Wutz, P. G. M. “Protecting Groups In Organic Synthesis” second edition,1991, New York, John Wiley & Sons, Inc.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine topoisomerase inhibition activityor cytotoxic activity using the standard tests described herein, orusing other similar tests which are well known in the art. Compounds ofthe present invention can contain chiral centers, for example, at ringatom position 6 in formula I when R₃ and R₄ are different. Compounds ofthe present invention can also contain chiral centers, for example, inany of the substituents Y, Z, R₁, R₂ when R₃ and R₄ together are ═N—R₂,and R₃ or R₄.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal, for example, sodium,potassium or lithium, or alkaline earth metal, for example calcium,salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, that is, orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, forexample, orally, in combination with a pharmaceutically acceptablevehicle such as an inert diluent or an assimilable edible carrier. Theymay be enclosed in hard or soft shell gelatin capsules, may becompressed into tablets, or may be incorporated directly with the foodof the patient's diet. For oral therapeutic administration, the activecompound may be combined with one or more excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 60% of theweight of a given unit dosage form. The amount of active compound insuch therapeutically useful compositions is such that an effectivedosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of formula I in a liquidcomposition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound may conveniently be administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The ability of a compound of the invention to effect topoisomerase I orII mediated DNA cleavage can be determined using pharmacological modelsthat are well known to the art, for example, using a model like Test Adescribed below.

Test A. Topoisomerase I-Mediated DNA Cleavage Assay

Human topoisomerase I was expressed in E. Coli and isolated as arecombinant fusion protein using a T7 expression system as describedpreviously, see Makhey, D. et al., Bioorg. Med. Chem., 2000, 8, 1-11.DNA topoisomerase I was purified from calf thymus gland as reportedpreviously, see Maniatis, T., et al., J. Molecular Cloning, a LaboratoryManual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.,149-185). Plasmid YepG was also purified by the alkali lysis methodfollowed by phenol deproteination and CsCl/ethidium isopycniccentrifugation method as described, see Maniatis, T., Fritsch, E. F.;Sambrook, J. Molecular Cloning, a Laboratory Manual; Cold Spring HarborLaboratory: Cold Spring Harbor, N.Y. 1982; pp 149-185. The end-labelingof the plasmid was accomplished by digestion with a restriction enzymefollowed by end-filling with Klenow polymerase as previously described,see Liu, L. F.; Rowe, T. C.; Yang, L.; Tewey, K. M.; Chen, G. L., J.Biol. Chem. 1983, 258, 15365. Cleavage assays were performed aspreviously reported, see B. Gatto et al. Cancer Res., 1996, 56,2795-2800. The drug and the DNA in presence of topoisomerase I wasincubated for 30 minutes at 37° C. After development of the gels,typically 24-hour exposure was used to obtain autoradiograms outliningthe extent of DNA fragmentation. Topoisomerase I-mediated DNA cleavagevalues are reported as REC, Relative Effective Concentration, i.e.concentrations relative to2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine, whose value isarbitrarily assumed as 1.0, that are able to produce the same cleavageon the plasmid DNA in the presence of human topoisomerase I. Relativepotency was based upon the relative amount of drug needed to induceapproximately 10% DNA fragmentation. Assays are performed under thedirection of Dr. L. F. Liu, Department of Pharmacology, The Universityof Medicine and Dentistry of New Jersey, Robert Wood Johnson MedicalSchool, Piscataway, N.J.

A similar assay can be used to evaluate the ability of a compound of theinvention to effect topoisomerase II mediated DNA cleavage, by replacingthe human topoisomerase I used in Test A with a suitable topoisomeraseII.

Camptothecin is recognized as being among the most potent topoisomeraseI inhibitors. Compound 5 has similar potency as a topoisomerase Iinhibitor to Irinotecan and Topotecan, both of which are in clinicaluse, as well as Camptothecin in the cleavable complex assay detailedherein.

TABLE 1 RPMI 8402 Compound [μM] IC₅₀ values CPT-K5 5 0.003 1.2Camptothecin 0.002 4.5 Irinotecan 0.57 >100 Topotecan 0.005 >10

The data in Table 1 demonstrate that a representative compound of thepresent invention can function as cytotoxic agents against tumor celllines.

The cytotoxic effects of a compound of the invention can be determinedusing pharmacological models that are well known to the art, forexample, using a model like Test B described below.

Test B. Inhibition of Cell Growth: MTT-Microtiter Plate TetrazoliniumCytotoxicity Assay (RPMI 8402, CPT-K5, U937, U937/CR Cells)

The cytotoxicity is determined using the MTT-microtiter platetetrazolinium cytotoxicity assay (MTA), see Chen A. Y. et al. CancerRes. 1993, 53, 1332; Mosmann, T. J., J. Immunol. Methods 1983, 65, 55;and Carmichael, J. et al. Cancer Res. 1987, 47, 936. The humanlymphoblast RPMI 8402 and its camptothecin-resistant variant cell line,CPT-K5 were provided by Dr. Toshiwo Andoh (Anchi Cancer ResearchInstitute, Nagoya, Japan), see Andoh, T.; Okada, K, Adv. in Pharmacology1994, 29B, 93. Human U-937 myeloid leukemia cells and U-937/CR cellswere described by Rubin et al., J. Biol. Chem., 1994, 269, 2433-2439.The cytotoxicity assay is performed by using 96-well microtiter platesusing 2000 cells/well, in 200 mL of growth medium. Cells are grown insuspension at 37° C. in 5% CO₂ and maintained by regular passage in RPMImedium supplemented with 10% heat-inactivated fetal bovine serum,L-glutamine (2 mM), penicillin (100 U/mL), and streptomycin (0.1 mg/mL).For determination of IC₅₀, cells are exposed continuously for 3-4 daysto varying concentrations of drug, and MTT assays were performed at theend of the fourth day. Each assay is performed with a control that didnot contain any drug. All assays are performed at least twice in 6replicate wells. All assays are performed under the direction of Dr. L.F. Liu, Department of Pharmacology, The University of Medicine andDentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway,N.J.

Topoisomerase inhibitors are also known to possess antibacterial,antifungal, antipsoritic (psoriasis), antiprotozoal, antihelmetic, andantiviral activity. Accordingly, the topoisomerase inhibitors of theinvention may also be useful as antibacterial, antifungal, antipsoritic(psoriasis), antiprotozoal, antihelmetic, or antiviral agents. Inparticular, compounds of the invention that demonstrate little or noactivity as mammalian topoisomerase I poisons, because of thepossibility of similar molecular mechanism of action, could be highlyactive and selective antibacterial, antifungal, antipsoritic(psoriasis), antiprotozoal, antihelmetic, or antiviral agents. Thus,certain compounds of the invention may be particularly useful assystemic antibacterial, antifungal, antipsoritic (psoriasis),antiprotozoal, antihelmetic, or antiviral agents in mammals. Theinvention also provides the use of a compound of the invention for themanufacture of a medicament useful for producing an antibacterial,antifungal, antipsoritic (psoriasis), antiprotozoal, antihelmetic, orantiviral effect in a mammal.

As used herein, the term “solid mammalian tumors” include cancers of thehead and neck, lung, mesothelioma, mediastinum, esophagus, stomach,pancreas, hepatobiliary system, small intestine, colon, rectum, anus,kidney, ureter, bladder, prostate, urethra, penis, testis, gynecologicalorgans, ovarian, breast, endocrine system, skin central nervous system;sarcomas of the soft tissue and bone; and melanoma of cutaneous andintraocular origin. The term “hematological malignancies” includeschildhood leukemia and lymphomas, Hodgkin's disease, lymphomas oflymphocytic and cutaneous origin, acute and chronic leukemia, plasmacell neoplasm and cancers associated with AIDS. The preferred mammalianspecies for treatment are humans and domesticated animals.

The invention will now be illustrated by the following non-limitingExamples, wherein unless otherwise stated: melting points weredetermined with a Thomas-Hoover Unimelt capillary melting pointapparatus; column chromatography refers to flash chromatographyconducted on SiliTech 32-63 m, (ICN Biomedicals, Eschwegge, Ger.) usingthe solvent systems indicated; radial chromatography refers to the useof a Model 8924 chromatotron (Harrison Research, CA); infrared spectraldata (IR) were obtained on a Perkin-Elmer 1600 Fourier transformspectrophotometer and are reported in cm⁻¹; proton (¹H NMR) and carbon(¹³C NMR) nuclear magnetic resonance were recorded on a VarianGemini-200 Fourier Transform spectrometer; NMR spectra (200 MHz ¹H and50 MHz ¹³C) were recorded in the deuterated solvent indicated withchemical shifts reported in units downfield from tetramethylsilane(TMS); coupling constants are reported in hertz (Hz); mass spectra wereobtained from Washington University Resource for Biomedical andBio-organic Mass Spectrometry within the Department of Chemistry atWashington University, St. Louis, Mo.; combustion analyses wereperformed by Atlantic Microlabs, Inc., Norcross, Ga., and were within0.4% of the theoretical value.

Specific compounds of the present invention can be prepared inaccordance with the following scheme using, for example, the reactionsand reagents illustrated.

Example 1

11,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-11-[2-(dimethylamino)ethyl]-5,6,11-triazachrysen-12-one(5). A mixture of4-N-(2-Dimethylaminoethyl)-N-(2-bromo-4,5-dimethoxybenzoyl)amine-6,7-methylenedioxycinnoline(4, 220 mg, 0.40 mmol), Pd(OAc)₂ (18.0 mg, 0.08 mmol), P(o-tolyl)₃ (48.8mg, 0.16 mmol), and silver carbonate (225 mg, 0.80 mmol) were heated toreflux in DMF (12 mL) and stirred under nitrogen for 75 minutes. Thereaction mixture was cooled to room temperature, diluted with chloroformand filtered though a bed of celite. The solvent was removed underreduced pressure and the resulting residue was chromatographed on silicagel using 95:5 chloroform:methanol to give the title compound (60 mg) in36% yield; ¹H NMR (CDCl₃) δ 2.42 (s, 6H), 3.04 (t, 2H, J=7.2 Hz), 4.08(s, 3H), 4.17 (s, 3H), 4.64 (t, 2H, J=7.2 Hz), 6.25 (s, 2H), 7.81 (s,1H), 7.84 (s, 1H), 8.07 (s, 1H), 8.65 (s, 1H); ¹³C NMR (CDCl₃) δ 45.9,47.4, 56.4, 56.7, 57.7, 99.4, 102.8, 104.3, 106.6, 107.9, 113.7, 119.6,129.1, 131.0, 134.4, 149.4, 150.2, 151.5, 154.4, 163.1; HRMS calcd. forC₂₂H₂₂O₅N₄H, 423.1668; found 423.1653.

The intermediate4-N-(2-Dimethylaminoethyl)-N-(2-bromo-4,5-dimethoxybenzoyl)amine-6,7-methylenedioxycinnoline(4) was prepared as follows:

a.4-N-(2-Dimethylaminoethyl)-N-(2-bromo-4,5-dimethoxybenzoyl)amine-6,7-methylenedioxycinnoline(4). A 2.0M solution of oxalyl chloride in methylene chloride (5 mL,10.0 mmol) was added to a solution of 2-iodo-4,5-dimethoxybenzoic acid(1.50 g, 4.8 mmol) in anhydrous methylene chloride (45 mL) and thestirred mixture was refluxed for 2 hours. The mixture was thenconcentrated to dryness under reduced pressure. To this residue wasadded a solution ofN-(2-Dimethylaminoethyl)-4-amino-6,7-methylenedioxycinnoline (3, 1.0 g,3.84 mmol), and triethylamine (760 mg 7.52 mmol) in methylene chloride(60 mL) and the resulting mixture was stirred at reflux under nitrogenfor 4 hours, then cooled to room temperature; stirring was continuedovernight. The reaction mix was washed with a saturated solution ofsodium bicarbonate (3×40 mL), dried (anhydrous MgSO₄), and concentratedin vacuo. The crude material was chromatographed over silica using 90:10chloroform:methanol to give compound 4 (1.59 g), in 75% yield; ¹H NMR(CDCl₃) δ 2.27 (s, 6H), 2.53 (m, 2H), 3.43 (s, 3H), 3.75 (s, 3H), 3.97(m, 1H), 4.44 (m, 1H), 6.24 (s, 1H), 6.25 (s, 1H), 6.43 (s, 1H), 7.02(s, 1H), 7.43 (s, 1H), 7.68 (s, 1H), 9.18 (s, 1H); ¹³C NMR (CDCl₃) δ45.5, 47.1, 55.7, 56.1, 56.7, 82.8, 96.7, 102.9, 105.4, 110.6, 121.9,123.2, 133.1, 136.0, 144.8, 148.2, 149.9, 150.9, 151.7, 152.4, 169.8;HRMS calcd for C₂₂H₂₃O₅N₄IH, 551.0791; found 551.0795.

b. N-(2-Dimethylaminoethyl)-4-amino-6,7-methylenedioxycinnoline (3).4-Chloro-6,7-methylenedioxycinnoline (350 mg, 1.7 mmol) and copperpowder (100 mg, 1.6 mmol) in N,N-dimethylethylenediamine (3.75 g, 42.6mmol) were stirred at 105° C. under nitrogen for 3 hours. ExcessN,N-dimethylethylenediamine was removed by rotoevaporation, and theresidue was dissolved in chloroform (50 mL), and washed with water (3×30mL), dried (anhydrous MgSO₄), and concentrated in vacuo to give compound3 (324 mg) in 74% yield; ¹H NMR (CDCl₃) δ 2.33 (s, 6H), 2.70 (t, 2H),3.38 (dt, 2H), 6.15 (s, 2H), 7.03 (s, 1H), 7.56 (s, 1H), 8.53 (s, 1H);¹³C NMR (CDCl₃) δ 39.5, 45.1, 57.0, 94.7, 102.1, 105.3, 112.7, 128.8,139.8, 147.8, 149.5, 150.7; HRMS calcd for C₁₃H₁₆O₂N₄: 260.1273; found260.1267.

c. 4-Chloro-6,7-methylenedioxycinnoline (2).4-Hydroxy-6,7-methylenedioxycinnoline (1, 1.0 g, 5.3 mmol) was added insmall portions to a stirred mixture of phosphorus pentachloride (1.4 g,6.7 mmol) and phosphorus oxychloride (4 mL, 6.6 mmol) at roomtemperature. The reaction flask was heated to 80° C. for 1 hour, thencooled to room temperature and poured onto 50 g of crushed ice. Afterneutralization of the solution with solid sodium acetate the precipitatewas removed by filtration and recrystallized from ethanol to give 800 mgof 4-chloro-6,7-methylenedioxycinnoline, compound 2, in 73% yield; ¹HNMR (CDCl₃) δ 6.25 (s, 2H), 7.39 (s, 1H), 7.73 (s, 1H), 9.14 (s, 1H);¹³C NMR (CDCl₃) δ 97.8, 102.9, 105.1, 124.2, 133.4, 144.0, 150.0, 152.3,152.7; HRMS calcd for C₉H₅O₂N₂Cl: 208.0040; found 208.0042.

d. 4-Hydroxy-6,7-methylenedioxycinnoline (1).6′-Amino-3′,4′-(methylenedioxy)acetophenone (2.4 g, 13.4 mmol) inconcentrated hydrochloric acid (92 mL) and water (13 mL) was cooled to−5° C. and a diazotized by the dropwise addition of a solution of sodiumnitrite (0.925 g, 13.4 mmol) in water (4 mL). After stirring for anadditional hour at −5° C. the mixture was transferred to a bathpreheated at 75° C. and left to stir at this temperature overnight. Thereaction mixture was cooled to 5° C. to complete crystallization of theproduct in the form of its hydrochloride salt. This material wasfiltered and then added to 10% aqueous NaOH (100 mL) to generate thefree base, which was again filtered and dried under vacuum to yield 2.37g of the hydroxycinnoline, compound 1, in 93% yield; ¹H NMR (d₆-DMSO) δ6.21 (s, 2H), 6.97 (s, 1H), 7.30 (s, 1H), 7.63 (s, 1H); ¹³C NMR(d₆-DMSO) δ 94.9, 100.29, 103.3, 120.1, 139.7, 139.9, 147.4, 153.5,169.4; HRMS calcd for C₉H₆O₃N₂: 190.0378; found 190.0372.

Examples 2-6

The representative compounds of the invention at Examples 2-6 wereprepared using the following general procedure from the intermediatesprepared in the correspondingly numbered sub-parts a below.

A mixture of the requisite 4-amino-6,7-methylenedioxycinnolineo-iodobenzamide derivative (1.0 mmol equiv.), Pd(OAc)₂ (0.2 mmolequiv.), P(o-tolyl)₃ (0.4 mmol equiv.), and Ag₂CO₃ (2.0 mmol equiv) washeated to reflux in DMF (30 mL per mmol equiv.) with stirring. Thereaction mixture was allowed to cool to room temperature, diluted withCHCl₃, and filtered through Celite. The sicciate was extensively washedwith 10% CH₃OH in CHCl₃. The filtrate was concentrated in vacuo and theresidue chromatographed on silica gel using chloroform:methanol toprovide the title compound.

Example 2

2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-diethylamino)ethyl]-11H-5,6,11-triaza-chrysen-12-one:Prepared fromN-(6,7-Methylenedioxycinnolin-4-yl)-N—(N,N-diethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide(578 mg, 1.0 mmol); (18% yield); reaction time 25 min; mp 245-247° C.(dec.); IR (CHCl₃) 1652; ¹H NMR (CDCl₃) δ 1.08 (t, 6H, J=7.0), 2.67 (q,4H, J=7.0), 3.14 (t, 2H, J=7.1), 4.08 (s, 3H), 4.17 (s, 3H), 4.64 (t,2H, J=7.1), 6.25 (s, 2H), 7.80 (s, 1H), 7.84 (s, 1H), 8.18 (s, 1H), 8.63(s, 1H); ¹³C NMR (CDCl₃) δ 11.8, 47.7, 48.0, 51.5, 56.4, 56.6, 99.7,102.7, 104.3, 106.4, 108.0, 113.7, 119.7, 129.1, 131.1, 134.4, 149.4,150.3, 151.2, 151.5, 154.4, 163.2; HRMS calcd for C₂₄H₂₆O₅N₄H, 451.1952;found: 451.1960.

Example 3

2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)-1-methylethyl]-11H-5,6,11-triaza-chrysen-12-one:Prepared fromN-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide(100 mg, 0.18 mmol); (28% yield); reaction time 2 h; mp 235-36° C.;IR(KBr) 1659: ¹H NMR (CDCl₃) δ 1.93 (d, 3H, J=8.2), 1.97 (s, 3H), 2.74(dd, 1H, J=5.8, 13.6), 3.27 (dd, 1H, J=7.4, 12.8), 4.07 (s, 3H), 4.15(s, 3H), 4.80 (m, 1H), 6.24 (s, 2H), 7.74 (s, 1H), 7.81 (s, 1H), 8.57(s, 1H); ¹³C(CDCl₃) δ 19.4, 45.6, 56.3, 58.6, 63.0, 99.0, 102.6, 104.1,106.2, 107.9, 114.2, 120.8, 125.6, 128.6, 131.0, 132.5, 132.8, 135.1,149.2, 150.3, 150.6, 151.3, 154.2, 164.0; HRMS calcd for C₂₃H₂₄N₄O₅H436.1747; found 436.1832.

Example 4

2,3-Dimethoxy-8,9-methylenedioxy-11-(2-tetrahydrofuranyl)methyl-11H-5,6,11-triazachrysen-12-one:Prepared fromN-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(tetrahydrofuran-2-yl)methyl]-2-iodo-4,5-dimethoxybenzamide(140 mg, 0.25 mmol); (22% yield); reaction time 45 min; mp 300-303° C.(dec.); IR(CHCl₃) 1653; ¹H NMR (CDCl₃) δ 1.79 (m, 1H), 2.00 (m, 2H),2.25 (m, 1H), 3.87 (m, 2H), 4.09 (s, 3H), 4.18 (s, 3H), 4.65 (m, 3H),6.25 (s, 2H), 7.80 (s, 1H), 7.84 (s, 1H), 8.32 (s, 1H), 8.63 (s, 1H);¹³C NMR (CDCl₃) δ 25.7, 30.8, 53.0, 56.4, 56.7, 68.4, 77.8, 100.0,102.7, 104.3, 106.3, 108.0, 114.1, 119.7, 129.1, 131.4, 134.5, 149.5,150.2, 150.8, 151.4, 154.4, 163.7; HRMS calcd for C₂₃H₂₁O₆N₃: 435.1430;found: 435.1427.

Example 5

2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(pyrrolidin-1-yl)ethyl]-11H-5,6,11-triaza-chrysen-12-one:Prepared fromN-(6,7-Methylenedioxycinnolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide(150 mg, 0.2 mmol) in 24% yield with a reaction time 30 min; mp 229° C.;IR (KBr) 1644; ¹H NMR (CDCl₃) δ 1.83 (m, 4H), 2.71 (m, 4H), 3.23 (t, 2H,J=7), 4.06 (s, 3H), 4.61 (s, 3H), 4.63 (t, 2H, J=7), 6.23 (s, 2H), 7.74(s, 1H), 7.80 (s, 1H); ¹³C NMR (CDCl₃) δ 23.7, 54.0, 54.2, 56.3, 56.6,99.4, 102.7, 104.2, 106.3, 107.7, 113.5, 119.4, 129.0, 134.1, 140.2,150.2, 151.4, 154.3, 154.3, 163.0; HRMS calcd for C₂₄H₂₄N₄O₅H, 449.1825;found 449.1822.

Example 6

2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(piperidin-1-yl)ethyl]-11H-5,6,11-triaza-chrysen-12-one:Prepared fromN-(6,7-Methylenedioxy-4-cinnolin-4-yl)-N-[2-(piperidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide(295 mg, 0.5 mmol); (32.4% yield); reaction time 30 min; mp 294-95° C.;IR (KBr) 1662; ¹HNMR (CDCl₃) δ 1.59 (s, 6H), 2.51 (s, 4H), 3.02 (t, 2H,J=6.6), 4.08 (s, 3H), 4.17 (s, 3H), 4.64 (t, 2H, J=6.6), 6.26 (s, 2H),7.81 (s, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 8.65 (s, 1H); ¹³C(CDCl₃) δ24.3, 26.0, 47.5, 55.0, 56.3, 56.6, 57.4, 99.9, 102.7, 104.2, 106.3,107.9, 113.7, 119.6, 129.0, 131.1, 134.3, 149.3, 150.2, 151.1, 151.4,154.3, 163.1; HRMS calcd for C₂₅H₂₆N₄O₅H 463.1981; found 463.1986.

Examples 2.a-6.a

The intermediate 4-amino-6,7-methylenedioxycinnoline o-iodobenzamidederivatives used in Examples 2-6 were prepared using the followinggeneral procedure.

A 2.0M solution of oxalyl chloride in CH₂Cl₂ (1.3 equiv.) was added to asolution of 2-iodo-4,5-dimethoxybenzoic acid (1.0 equiv.) in anhydrousCH₂Cl₂ (≈60 mL per 10 mmol benzoic acid) and the solution stirred atreflux for 3 h. The mixture was allowed to cool and was thenconcentrated to dryness in vacuo. To the residues was added a solutionof requsite 4-amino-6,7-dimethoxyquinoline (1.0 equiv), triethylamine (2equiv.) in CH₂Cl₂ (≈60 mL per 4 mmol aminoquinoline). The reactionmixture was then stirred at reflux under N₂. The reaction mixture wascooled and washed with sat. NaHCO₃ and extracted with 3% HCl. Theaqueous layer was neutralized with 20% NaOH and extracted with CHCl₃,dried (MgSO₄) and evaporated.

Example 2.a

N-(6,7-Methylenedioxycinnolin-4-yl)-N—(N,N-diethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide:Prepared fromN′-(6,7-Methylenedioxycinnolin-4-yl)-N,N-diethylethane-1,2-diamine (640mg, 2.2 mmol); (87% yield); reaction time 16 h; IR (CHCl₃) 1656; ¹H NMR(CDCl₃) δ 0.92 (t, 6H, J=7.0), 2.50 (q, 4H, J=7.0), 2.80 (t, 2H, J=6.8),3.39 (s, 3H), 3.71 (s, 3H), 3.94 (m, 1H), 4.41 (m, 1H), 6.21 (d, 2H,J=1.4), 6.39 (s, 1H), 7.01 (s, 1H), 7.39 (s, 1H), 7.64 (s, 1H), 9.11 (s,1H); ¹³C NMR (CDCl₃) δ 11.6, 46.9, 47.8, 51.1, 55.7, 56.1, 82.9, 96.9,102.9, 105.5, 110.9, 122.1, 122.9, 133.0, 136.5, 144.9, 148.3, 150.1,150.9, 151.7, 152.3, 169.8; HRMS calcd for C₂₄H₂₇O₅N₄IH, 579.1105;found: 579.1105.

Example 3.a

N-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide:Prepared fromN-(6,7-difluorocinnolin-4-yl)-N¹,N¹-dimethylpropane-1,2-diamine (240 mg,0.87 mmol); (83% yield); reaction time 16 h, mp 110-111° C.; ¹H NMR(CDCl₃) was a mixture of atropisomers δ isomer #1 1.03-1.36 (m, 3H),2.21-2.37 (m, 6H), 2.74-3.07 (m, 1H), 3.43-3.65 (m, 6H), 3.84-3.91 (m,1H), 5.15 (m, 1H), 6.18 (s, 2H), 6.59 (s, 1H), 6.91 (s, 1H), 7.56 (s,1H), 8.04 (s, 1H), 9.34 (s, 1H) isomer #2 1.03-1.36 (m, 3H), 2.31-2.37(m, 6H), 2.74-3.07 (m, 1H), 3.43-3.65 (m, 6H), 3.84-3.91 (m, 1H), 5.15(m, 1H), 6.18 (s, 21H), 6.59 (s, 1H), 6.91 (s, 1H), 7.56 (s, 1H), 8.04(s, 1H), 9.34 (s, 1H); HRMS calcd for C₂₃H₂₅O₅N₄IH, 565.0870; found:565.0926.

Example 4.a

N-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(tetrahydrofuran-2-yl)methyl]-2-iodo-4,5-dimethoxybenzamide:Prepared from2-[[[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]methyl]tetrahydrofuran(400 mg, 1.5 mmol); (34% yield); reaction time 16 h; IR (CHCl₃) 1654; ¹HNMR, a mixture of atropisomers, (CDCl₃) δ isomer #1 1.94 (m, 4H), 3.70(m, 4H), 3.73 (s, 3H), 3.94 (s, 3H), 4.34 (m, 1H) 6.23 (s, 2H), 7.00 (s,1H), 7.40 (s, 1H), 7.70 (s, 1H), 9.31 (s, 1H), isomer #2 1.94 (m, 4H),3.70 (m, 4H), 3.73 (s, 3H), 3.94 (s, 3H), 4.34 (m, 1H) 6.46 (s, 2H),7.36 (s, H), 7.49 (s, 1H), 7.65 (s, 1H), 9.17 (s, 1H); HRMS calcd forC₂₃H₂₂O₆N₃IH, 564.0632; found: 564.0650.

Example 5.a

N-(6,7-Methylenedioxycinnolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide:Prepared from1-[2-[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]ethylpyrrolidine (400mg, 0.4 mmol) in 42% yield with a reaction time 4 h at 50° C. from theacid chloride prepared using 4.1 mmol of oxalyl chloride and 1.6 mmol of2-iodo-4,5-dimethoxybenzoic acid. Compound 8f had: IR (KBr) 1655; ¹H NMR(CDCl₃) δ 1.60 (m, 4H), 2.40 (m, 4H), 2.67 (m, 2H), 3.28 (s, 3H), 3.60(s, 3H), 4.32 (m, 1H), 6.11 (d, 2H, J=2.2), 6.32 (s, 1H), 6.91 (s, 1H),7.37 (s, 1H), 7.50 (s 1H), 9.04 (s, 1H); ¹³C NMR (CDCl₃) δ 23.6, 29.7,47.6, 52.9, 53.9, 55.7, 56.0, 56.4, 82.8, 96.7, 102.9, 105.4, 110.6,121.9, 123.1, 132.8, 135.9, 144.7, 148.2, 149.9, 150.9, 151.7, 152.4,169.9.

Example 6.a

N-(6,7-Methylenedioxy-4-cinnolin-4-yl)-N-[2-(piperidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide:Prepared from1-[2-[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]ethylpiperidine (500 mg,1.66 mmol); (85.4% yield); reaction time overnight at 50° C. mp 93-94°C.; IR (KBr) 1655; ¹HNMR (CDCl₃) δ 1.43 (m, 6H), 2.35 (m, 4H), 2.50-2.71(m, 2H), 3.43 (s, 3H), 3.73 (s, 3H), 3.78-3.93 (m, 1H), 4.32-4.42 (m,1H), 6.22 (d, 2H, J=1.6), 6.42 (s, 1H), 7.02 (s, 1H), 7.47 (s, 1H), 7.66(s, 1H), 9.19 (s, 1H); ¹³C (CDCl₃) δ 24.3, 25.9, 46.0, 46.4, 54.5, 55.6,56.0, 56.4, 82.9, 97.0, 102.8, 105.3, 110.8, 122.0, 113.7, 123.2, 133.1,136.3, 145.0, 148.2, 149.9, 150.8, 151.6, 152.1, 169.8 HRMS calcd forC₂₃H₂₅₁N₄O₅H, 591.1105; found 591.1108.

Examples 2.b-6.b

The intermediate 4-amino-6,7-dimethoxyquinoline derivatives used inExamples 2.a-6.a. were prepared using the following general procedure.

The appropriate primary amine (1.0 mol equiv.) added with stirring to4-Chloro-6,7-methylenedioxycinnoline (see Example 1 above). The reactionwas then allowed to stir at 100° C. for several hours, and the phenolremoved by Kugelrohr distillation under reduced pressure. The residuewas partitioned between CHCl₃ and 10% NaOH. The aqueous layer wasrepeatedly separated with CHCl₃. All of the CHCl₃ solutions (initialpartition and extracts) were combined and dried (MgSO₄).

Example 2.b

N′-(6,7-Methylenedioxycinnolin-4-yl)-N,N-diethylethane-1,2-diamine:Prepared from 4-Chloro-6,7-methylenedioxycinnoline (1.0 g, 4.8 mmol);(70% yield); reaction time 3 h; mp 230-232° C.; ¹H NMR (CDCl₃) δ 1.10(t, 6H, J=7.2), 2.63 (q, 4H, J=7.2), 2.84 (t, 2H, J=5.7), 3.35 (q, 2H,J=5.7), 5.78 (br, 1H), 6.15 (s, 2H), 6.96 (s, 1H), 7.57 (s, 1H), 8.52(s, 1H); ¹³C NMR (CDCl₃) δ 12.2, 39.5, 46.6, 50.8, 94.4, 102.0, 105.4,112.8, 129.0, 139.8, 147.8, 149.5, 150.7; HRMS calcd for C₁₅H₂₀O₂N₄:288.1586; found: 288.1575.

Example 3.b

N-(6,7-difluorocinnolin-4-yl)-N¹,N¹-dimethylpropane-1,2-diamine:Prepared from 4-Chloro-6,7-methylenedioxycinnoline (0.52 g, 2.5 mmol);(42% yield), reaction time 4 h, mp 196-197° C.;; ¹H NMR (CD₃OD) δ 1.31(d, 3H, J=6.6), 2.33 (s, 6H), 2.45 (dd, 1H, J=5.4, 12.8), 2.74 (dd, 1H,J=8.2, 12.6), 4.12 (dd, 1H, J=5.8, 13.8), 6.19 (s, 2H), 7.32 (s, 1H),7.56 (s, 1H), 8.51 (s, 1H); ¹³C NMR (CD₃OD) δ 17.1, 44.0, 45.3, 63.5,95.1, 101.6, 102.0, 112.6, 126.7, 140.8, 149.3, 151.2; HRMS calcd forC₁₄H₁₈O₂N₄: 274.1430; found: 274.1429.

Example 4.b

2-[[[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]methyl]tetrahydrofuran:prepared from 4-Chloro-6,7-methylenedioxycinnoline (500 mg, 2.4 mmol);(78% yield); reaction time 2 h; mp 196-198° C.; ¹H NMR (CDCl₃) δ 1.74(m, 1H), 2.11 (m, 3H), 3.30 (m, 1H), 3.58 (m, 1H), 3.92 (m, 2H), 4.29(m, 1H), 5.22 (br, 1H), 6.12 (s, 2H), 6.98 (s, 1H), 7.52 (s, 1H), 8.54(s, 1H); ¹³C NMR (CDCl₃) δ 25.9, 29.2, 46.9, 68.4, 76.9, 94.4, 102.2,105.2, 112.8, 128.7, 139.8, 147.9, 149.6, 150.8; HRMS calcd forC₁₄H₁₅O₃N₃: 273.1130; found: 273.1130.

Example 5.b

1-[2-[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]ethylpyrrolidine:Prepared from 4-Chloro-6,7-methylenedioxycinnoline (750 mg, 3.5 mmol),1-(2-aminoethyl)pyrrolidine (3 ml) and copper powder (300 mg) in 75%yield; reaction time 18 h at 90° C.; mp 215° C. (dec); ¹H NMR (CDCl₃) δ1.85 (m, 4H), 2.63 (m, 4H), 2.90 (t, 2H, J=6), 3.42 (t, 2H, J=6), 5.63(s, 1H), 6.14 (s, 2H), 7.04 (s, 1H), 7.57 (s, 1H), 8.53 (s, 1H); ¹³C NMR(DMSO-d₆) δ 23.9, 42.0, 54.5, 54.7, 97.0, 102.9, 104.4, 112.7, 126.8,140.8, 149.3, 151.0; HRMS calcd for C₁₅H₁₈N₄O₂: 293.1590; found293.1579.

Example 6.b

1-[2-[N-(6,7-Methylenedioxycinnolin-4-yl)]amino]ethylpiperidine:Prepared from 4-Chloro-6,7-methylenedioxycinnoline (1.04 g, 5.0 mmol);(37% yield); reaction time 2 h; mp 238-239° C.; ¹H NMR (CD₃OD) δ 1.56(d, 2H, J=5.2), 1.70 (d, 2H, J=4.6), 2.87 (t, 2H, J=7), 3.65 (t, 2H,J=6.6), 6.20 (s, 2H), 7.32 (s, 1H), 7.43 (s, 1H), 8.46 (s, 1H); ¹³C(CD₃OD) δ 23.1, 24.7, 38.5, 53.6, 56.1, 94.7, 101.7, 102.1, 112.4,126.6, 141.1, 14.7, 149.4, 151.2 (CDCl₃); HRMS calcd for C₁₆H₂₀N₄O₂H,300.1586; found 300.1586.

Examples 7-12

The representative compounds of the invention at Examples 7-12 wereprepared using the following general procedure from the intermediatesprepared in the correspondingly numbered sub-parts a below.

A mixture of the requsite 4-amino-6,7-methylenedioxyquinolineo-iodobenzamide derivative (1.0 mmol equiv.), Pd(OAc)₂ (0.2 mmolequiv.), P(o-tolyl)₃ (0.4 mmol equiv.), and Ag₂CO₃ (2.0 mmol equiv) washeated to reflux in DMF (30 mL per mmol equiv.) with stirring. Thereaction mixture was allowed to cool to room temperature, diluted withCHCl₃, and filtered through Celite. The sicciate was extensively washedwith 10% CH₃OH in CHCl₃. The filtrate was concentrated in vacuo and theresidue chromatographed on silica gel using chloroform:methanol.

Example 7

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N—(N,N-dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide;(41% yield); reaction time 25 min; mp 283-285° C. (dec.); IR (CHCl₃)1653; ¹H NMR (CDCl₃) δ 2.33 (s, 6H), 3.04 (t, 2H, J=7.2), 4.07 (s, 3H),4.14 (s, 3H), 4.64 (t, 2H, J=7.2), 6.18 (s, 2H), 7.47 (s, 1H), 7.68 (s,1H), 7.89 (s, 2H), 9.37 (s, 1H); ¹³C NMR (CDCl₃) δ 45.9, 49.2, 56.3,56.3, 57.9, 101.2, 102.0, 102.3, 107.1, 108.8, 111.7, 114.8, 119.3,127.6, 140.9, 143.5, 147.3, 147.7, 149.9, 150.3, 154.2, 164.1; HRMScalcd for C₂₃H₂₃N₃O₅H, 422.1716; found 422.1710.

Example 8

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide;(30.4% yield); reaction time 30 min; mp 186-187° C.; IR (KBr) 1649; ¹HNMR (CDCl₃); δ 1.95-1.98 (m, 9H), 2.77 (dd, 1H, J=12.0, 8.0), 3.21 (dd,1H, J=12.0, 8.0), 4.06 (s, 3H), 4.13 (s, 3H), 4.84-4.92 (m, 1H), 6.17(s, 2H), 7.46 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 7.87 (s, 1H), 9.35(s, 1H); ¹³C NMR (CDCl₃) δ 19.7, 45.5, 56.2, 56.3, 59.5, 63.1, 100.9,101.9, 102.1, 107.0, 108.7, 112.4, 115.2, 120.5, 127.3, 142.6, 143.3,147.0, 147.3, 149.9, 150.1, 154.0, 164.9; HRMS calcd for C₂₄H₂₅N₃O₅H,436.1794; found 436.1863.

Example 9

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(pyrrolidin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide;(36% yield); reaction time 30 min; mp 255-257° C. (dec.); IR(CHCl₃)1653; ¹H NMR (CDCl₃) δ 1.79 (m, 4H), 2.64 (m, 4H), 3.20 (t, 2H, J=7.1),4.07 (s, 3H), 4.14 (s, 3H), 4.69 (t, 2H, J=7.1), 6.18 (s, 2H), 7.46 (s,1H), 7.68 (s, 1H), 7.89 (s, 1H), 7.95 (s, 1H), 9.37 (s, 1H); ¹³C NMR(CDCl₃) δ 23.7, 49.6, 54.3, 56.3, 56.4, 56.4, 101.3, 102.0, 102.3,107.0, 108.7, 111.7, 114.8, 119.3, 127.7, 140.9, 143.4, 147.3, 147.8,150.0, 150.3, 154.2, 164.2; HRMS calcd for C₂₅H₂₅N₃O₅H, 448.1872; found448.1872.

Example 10

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(4-methylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(4-methyl-1-piperazinyl)ethyl]-2-iodo-4,5-dimethoxybenzamide;(18% yield); reaction time 25 min; mp 244-246° C.; IR (CHCl₃) 1651; ¹HNMR (CDCl₃) δ 2.27 (s, 3H), 2.51 (m, 8H), 2.95 (t, 2H, J=6.2), 4.07 (s,3H), 4.15 (s, 3H), 4.69 (t, 2H, J=6.2), 6.19 (s, 2H), 7.48 (s, 1H), 7.70(s, 1H), 7.91 (s, 2H), 7.92 (s, 1H), 9.39 (s, 1H); ¹³C NMR (CDCl₃) δ29.8, 45.9, 48.6, 53.0, 55.0, 56.4, 56.4, 101.2, 102.0, 102.2, 107.1,108.9, 112.0, 115.0, 119.5, 127.6, 141.2, 143.4, 147.4, 147.2, 150.0,150.3, 154.1, 164.4; HRMS calcd for C₂₆H₂₈N₄O₅H, 477.2138; found477.2139.

Example 11

8,9-Dimethoxy-2,3-methylenedioxy-5-[3-(N,N-dimethylamino)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one):Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[3-(N,N-dimethylamino)propyl]-2-iodo-4,5-dimethoxybenzamide;(45% yield); reaction time 30 min; mp 262-264° C. (dec.); IR(CHCl₃)1648; ¹H NMR (CDCl₃) δ 2.29 (m, 8H), 2.45 (m, 2H), 4.07 (s, 3H), 4.14(s, 3H), 4.53 (t, 2H, J=7.4), 6.19 (s, 2H), 7.48 (s, 1H), 7.65 (s, 1H),7.69 (s, 1H), 7.90 (s, 1H), 9.40 (s, 1H); ¹³C NMR (CDCl₃) δ 26.9, 45.3,49.2, 56.3, 56.4, 56.9, 100.8, 101.9, 102.3, 107.1, 108.7, 111.6, 114.9,119.4, 127.5, 141.0, 143.6, 147.2, 147.7, 149.9, 150.3, 154.1, 164.1;HRMS calcd for C₂₄H₂₅N₃O₅H, 436.1872; found 436.1878.

Example 12

8,9-Dimethoxy-2,3-methylenedioxy-5-(2-tetrahydrofuranyl)methyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(tetrahydrofuran-2-yl)methyl]-2-iodo-4,5-dimethoxybenzamide;(22% yield); reaction time 30 min; mp 270-273° C.; IR(CHCl₃) 1648; ¹HNMR (CDCl₃) δ 1.87 (m, 4H), 3.72 (m, 2H), 4.07 (s, 3H), 4.14 (s, 3H),4.68 (m, 3H), 6.18 (s, 2H), 7.48 (s, 1H), 7.69 (s, 1H), 7.90 (s, 1H),8.04 (s, 1H), 9.39 (s, 1H); ¹³C NMR (CDCl₃) δ 25.6, 30.3, 54.7, 56.3,56.4, 68.1, 77.3, 101.7, 102.2, 102.3, 107.0, 109.0, 112.1, 115.2,119.5, 127.7, 141.2, 143.5, 147.2, 147.4, 149.9, 150.3, 154.2, 164.6;HRMS calcd for C₂₄H₂₂N₂O₆H 435.1556; found 435.1566.

Examples 7.a-12.a

The intermediate 4-amino-6,7-methylenedioxyquinoline o-iodobenzamidederivatives used in Examples 7-12 were prepared using the followinggeneral procedure.

A 2.0M solution of oxalyl chloride in CH₂Cl₂ (1.3 equiv.) was added to asolution of 2-iodo-5,6-dimethoxybenzoic acid (1.0 equiv.) in anhydrousCH₂Cl₂ (≈60 mL per 10 mmol benzoic acid) and the solution stirred atreflux for 3 h. The mixture was allowed to cool and was thenconcentrated to dryness in vacuo. To the residue was added a solution ofappropriate 4-amino-6,7-dimethoxyquinoline (1.0 equiv), triethylamine (2equiv.) in CH₂Cl₂ (≈60 mL per 4 mmol aminoquinoline). The reactionmixture was then stirred at reflux under N₂. In the case of thosederivatives that have an alkylamine incorporated in their structure, theresidue was partitioned between CHCl₃ and 10% NaOH. The aqueous layerwas repeatedly separated with CHCl₃. All of the CHCl₃ solutions (initialpartition and extracts) were combined and dried (MgSO₄). The aqueouslayer was neutralized with 20% NaOH and extracted with CHCl₃, dried(MgSO₄) and evaporated.

Example 7.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N—(N,N-dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide.Prepared fromN′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylethane-1,2-diamine (1.0g, 3.84 mmol) in 71% yield with a reaction time of 3 h, from the acidchloride prepared using 10 mmol of oxalyl chloride and 4.8 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 7a had: IR(CHCl₃) 1652; ¹HNMR (CDCl₃) δ 2.74 (s, 6H), 2.66 (t, 2.H, J=7.0), 3.33 (s, 3H), 3.74 (s,3H), 3.96 (m, 1H), 4.49, (m, 1H), 6.15 (s, 2H), 6.41 (s, 1H), 7.03 (s,1H), 7.34 (d, 1H, J=4.8), 7.37 (s, 1H), 7.44 (s, 1H), 8.56 (d, 1H,J=4.8); ¹³C NMR (CDCl₃) δ 45.7, 46.9, 55.5, 56.1, 56.6, 82.7, 98.5,102.2, 106.7, 110.2, 120.2, 121.5, 122.9, 121.5, 122.9, 133.8, 145.9,148.0, 148.3, 148.5, 149.0, 149.6, 151.0, 170.0; HRMS calcd forC₂₃H₂₄IN₃O₅H, 550.0839; found 550.0823.

Example 8.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide.Prepared fromN′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,2-diamine(273 mg, 1.0 mol) in 60.4% yield with a reaction time of 12 h, from theacid chloride prepared using 4.8 mmol of oxalyl chloride and 1.2 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 7b had: mp 82-84° C.; IR(KBr) 1648, 3415; HRMS calcd for C₂₄H₂₆₁N₃O₅H 564.0917; found 564.0997

Example 9.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide.Prepared from1-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethylpyrrolidine (285mg, 1.0 mmol), in 87% yield with a reaction time of 12 h, from the acidchloride prepared using 4 mmol of oxalyl chloride and 1.36 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 7c had: IR(CHCl₃) 1650; ¹HNMR (CDCl₃) δ 1.78 (m, 4H), 2.22 (m, 1H), 2.59 (m, 3H), 2.83 (t, 2H,J=6.6), 3.33 (s, 3H), 3.74 (s, 3H), 3.96 (d, 1H, J=4), 4.54 (m, 1H),6.15 (s, 1H), 6.42 (s, 1H), 7.03 (s, 1H), 7.34 (d, 1H, J=4.8), 7.36 (s,1H), 7.44 (s, 1H), 8.55 (d, 1H, J=4.8); ¹³C NMR (CDCl₃) δ 23.7, 47.7,52.9, 54.1, 55.5, 56.1, 82.7, 98.4, 102.2, 106.7, 106.7, 120.1, 121.5,122.9, 133.7, 145.9, 148.0, 148.3, 148.4, 149.0, 149.6, 151.0, 170.0;HRMS calcd for C₂₅H₂₆IN₃O₅H, 576.0995; found 576.1003.

Example 10.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(4-methyl-1-piperazinyl)ethyl]-2-iodo-4,5-dimethoxybenzamide.Prepared from1-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethyl-4-methylpiperazine(290 mg, 0.9 mmol) in 50% yield with a reaction time of 12 h, from theacid chloride prepared using 4.0 mmol of oxalyl chloride and 1.8 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 7d had: IR(CHCl₃) 1649; ¹HNMR (CDCl₃) δ 2.29 (s, 3H), 2.51 (m, 10H), 3.35 (s, 3H), 3.75 (s, 3H),3.95 (m, 1H), 4.46 (m, 1H), 6.15 (s, 1H), 6.42 (s, 1H), 7.03 (s, 1H),7.35 (d, 1H, J=4.6), 7.36 (s, 1H), 7.48 (s, 1H), 8.57 (d, 1H, J=4.6);¹³C NMR (CDCl₃) δ 46.0, 46.2, 53.1, 55.2, 55.5, 55.5, 56.0, 82.7, 98.7,102.2, 106.7, 110.4, 120.3, 121.6, 123.0, 133.7, 146.0, 148.0, 148.4,148.4, 148.9, 149.6, 151.0, 170.0; HRMS calcd for C₂₆H₂₉IN₄O₅H,605.1261; found 605.1261.

Example 11.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[3-(N,N-dimethylamino)propyl]-2-iodo-4,5-dimethoxybenzamide.Prepared fromN′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,3-diamine(273 mg, 1.0 mmol), in 79% yield with a reaction time of 12 h, from theacid chloride prepared using 4.0 mmol of oxalyl chloride and 1.36 mmolof 2-iodo-5,6-dimethoxybenzoic acid. Compound 7e had: IR(CHCl₃) 1650; ¹HNMR (CDCl₃) δ 1.93 (m, 1H), 2.16 (m, 1H), 2.34 (s, 6H), 2.58 (m, 1H),3.31 (s, 3H), 3.47 (m, 1H), 3.75 (s, 3H), 3.95 (m, 1H,), 4.55, (m, 1H),6.16 (s, 1H), 6.39 (s, 1H), 7.04 (s, 1H), 7.28 (d, 1H, J=5.0), 7.31 (s,1H), 7.38 (s, 1H), 8.56 (d, 1 h, J=5.0); ¹³C NMR (CDCl₃) δ 25.8, 45.1,47.2, 55.5, 56.1, 26.9, 82.7, 98.1, 102.3, 107.0, 110.1, 120.1, 121.5,122.5, 133.5, 145.5, 148.1, 148.4, 148.6, 149.2, 149.7, 151.1, 170.1;HRMS calcd for C₂₄H₂₆IN₃O₅H, 564.0995; found 564.0990.

Example 12.a

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(tetrahydrofuran-2-yl)methyl]-2-iodo-4,5-dimethoxybenzamide.Prepared from2-[[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]methyl]tetrahydrofuran(272 mg, 1.0 mol) in 36% yield with a reaction time of 16 h, from theacid chloride prepared using 4.0 mmol of oxalyl chloride and 1.36 mmolof 2-iodo-5,6-dimethoxybenzoic acid. Compound 7g had: IR(CHCl₃) 1652;HRMS calcd for C₂₄H₂₃N₂O₆₁H, 563.0679; found 563.0703.

Examples 7.b-12.b

The intermediate 4-amino-6,7-dimethoxyquinoline derivatives used inExamples 7.a-12.a. were prepared using the following general procedure.

4-Chloro-6,7-methylenedioxyquinoline was stirred in refluxing phenol(5.5 mol equiv.) for 2.5 h. The temperature was lowered to 100° C. andthe primary amine (1.0 mol equiv.) added with stirring. The reaction wasthen allowed to stir at 100° C. for several hours, and the phenolremoved by Kugelrohr distillation under reduced pressure. In the case ofthose derivatives that have an alkylamine incorporated in theirstructure, the residue was partitioned between CHCl₃ and 10% NaOH. Theaqueous layer was repeatedly separated with CHCl₃. All of the CHCl₃solutions (initial partition and extracts) were combined and dried(MgSO₄). Other 4-amino-6,7-methylenedioxyquinoline derivatives werepurified by column chromatography.

Example 7.b

N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylethane-1,2-diamine wasprepared from N,N-dimethylethylenediamine (2.55 g, 29 mmol) in 54% yieldwith a reaction time of 24 h. Compound 6a had: mp 193-194° C.; ¹H NMR(CDCl₃) δ 2.32 (s, 6H), 2.70 (t, 2H, J=6.6), 3.29 (m, 2H), 5.62 (br,1H), 6.10 (s, 2H), 6.36 (d, 1H, J=5.3), 7.10 (s, 1H), 7.34 (s, 1H), 8.40(d, 1H, J=5.3); ¹³C NMR (CDCl₃) δ 40.1, 45.2, 57.2, 96.3, 98.9, 101.6,106.5, 114.4, 145.2, 146.8, 148.9, 149.7, 150.1; HRMS calcd forC₁₄H₁₇N₃O₂: 260.1399; found 260.1377.

Example 8.b

N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,2-diamine wasprepared from 2-methyl-2-(N,N-dimethylamino)ethylamine (2.55 g, 29 mmol)from in 30.7% yield with a reaction time of 24 h. Compound 6b had: mp71-72° C.; ¹H NMR (CD₃OD); δ 1.26 (d, 3H, J=5.6), 3.22 (s, 6H), 2.41(dd, 1H, J=6.2, 12), 2.65 (dd, 1H, J=5.8, 12.2), 3.82-3.86 (m, 1H), 6.16(s, 2H), 6.46 (d, 1H, J=5.8), 7.16 (s, 1H), 7.45 s, 1H), 8.20 (d, 1H,J=6.0); ¹³C NMR δ 17.1, 44.0, 45.4, 63.6, 96.6, 97.3, 101.3, 101.8,113.9, 144.8, 146.3, 146.8, 149.7, 150.0; HRMS calcd for C₁₅H₁₉N₃O₂H,273.1484; found 273.1477.

Example 9.b

1-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethylpyrrolidine wasprepared from 1-(2-aminoethyl)pyrrolidine (1.14 g, 10.0 mmol) in 31%yield with a reaction time of 20 h. Compound 6c had: mp 179-182° C.; ¹HNMR (CDCl₃) δ 1.83 (m, 4H), 2.60 (m, 4H), 2.87 (t, 2H, J=5.9), 3.33 (m,2H), 5.58 (br, 1H), 6.08 (s, 2H), 6.34 (d, 1H, J=5.1), 7.08 (s, 1H),7.31 (s, 1H), 8.40 (d, 1H, J=5.1); ¹³C NMR (CDCl₃) δ 23.7, 41.4, 53.9,54.0, 96.3, 98.9, 101.6, 106.6, 114.4, 146.4, 146.7, 149.1, 149.6,150.0; HRMS calcd for C₁₆H₁₉N₃O₂: 285.1477; found 285.1468.

Example 10.b

1-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethyl-4-methylpiperazinewas prepared from 2-(4-methylpiperidin-1-yl)ethylamine (1.43 g, 10.0mmol) in 20% yield with a reaction time of 24 h. Compound 6d had: mp159-161° C.; ¹H NMR (CDCl₃) δ 2.34 (s, 3H), 2.54 (m, 10H), 2.80 (t, 2H,J=5.9), 5.62 (br, 1H), 6.11 (s, 2H), 6.38 (d, 1H, J=5.2), 7.05 (s, 1H),7.33 (s, 1H), 8.41 (d, 11H, J=5.2); ¹³C NMR (CDCl₃) δ 39.1, 46.2, 52.7,55.4, 55.7, 96.0, 99.0, 101.6, 106.6, 114.3, 146.8, 146.8, 149.0, 149.5,150.0; HRMS calcd for C₁₇H₂₂N₄O₂: 314.1743; found 314.1738.

Example 11.b

N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-1,3-diamine wasprepared from N,N-dimethyl-1,3-diaminopropane (1.0 g, 10.0 mmol) in 25%yield with a reaction time of 20 h. Compound 6e had: mp 178-181° C.; ¹HNMR (CDCl₃) δ 1.92 (m, 2H), 2.39 (s, 6H), 2.58 (t, 2H, J=5.5), 3.39 (m,2H), 6.08 (s, 2H), 6.29 (d, 1H, J=5.6), 6.95 (s, 1H), 7.31 (s, 1H), 7.52(br s, 1H), 8.37 (d, 1H, J=5.6); ¹³C NMR (CDCl₃) δ 24.6, 44.4, 45.7,59.7, 96.6, 98.0, 101.5, 106.4, 114.5, 146.2, 146.6, 148.9, 149.9,150.5; HRMS calcd for C₁₅H₁₉N₃O₂: 273.1477; found 273.1473.

Example 12.b

2-[[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]methyl]tetrahydrofuranwas prepared from tetrahydrofurfurylamine (1.01 g, 10.0 mmol) in 84%yield with a reaction time of 20 h. Compound 6g had: mp 276-278° C.; ¹HNMR (CD₃OD) δ 1.77 (m, 1H), 2.07 (m, 3H), 3.61 (m, 2H), 3.86 (m, 2H),4.26 (m, 1H), 6.28 (s, 2H), 6.90 (d, 1H, J=7.1), 7.19 (s, 1H), 7.74 (s,1H), 8.21 (d, 1H, J=7.1); ¹³C NMR (CDCl₃) δ 24.7, 28.1, 46.6, 67.3,76.7, 96.5, 97.6, 97.8, 103.1, 112.2, 135.8, 138.6, 148.3, 153.2, 155.1;HRMS calcd for C₁₅H₁₆N₂O₃: 272.1161; found 272.1172.

The intermediate 4-Chloro-6,7-methylenedioxyquinoline was prepared asfollows.

Diethyl 3,4-methylenedioxyanilinomethylene malonate.3,4-Methylenedioxyaniline (41.0 g, 0.3 mmol) and diethylethoxymethylenemalonate (64.8 g, 0.3 mmol) were refluxed in benzene for3.5 hours. The solvent was evaporated in vacuo and the residue waswashed with petroleum ether to give 88.3 g as a shiny grey-brown solid,in 96% yield; mp 99.5-101.0° C. (lit.²²¹ mp 102° C.); ¹H NMR (CDCl₃) δ1.34 (t, 3H, J=7.0), 1.40 (t, 3H, J=7.0) 4.25 (q, 2H, J=7.0), 4.31 (q,2H, J=7.0), 6.01 (s, 2H), 6.60 (dd, 1H, J=8.5, J=2.2), 6.71 (d, 1H,J=2.2), 6.81 (d, 1H, J=8.5), 8.41 (d, 1H, J=14.0); ¹³C NMR (CDCl₃) δ14.4, 14.6, 60.1, 60.4, 92.9, 99.4, 101.8, 108.9, 110.9, 134.3, 145.3,148.9, 152.6, 165.8, 169.3.

4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl ester.Diethyl 3,4-methylenedioxyanilinomethylene malonate (80.0 g, 0.261 mol)was stirred in polyphosphate ester (PPE) (250 g, 0.528 mol) at 120° C.with a mechanical stirrer for 2 hours. The reaction mixture was pouredinto ice water (700 mL) and stirred until homogenous. The mixture wasthen neutralized (pH 8) with ammonium hydroxide, and the precipitate wasfiltered, washed well with water, and dried to give 54.7 g as a brownsolid, in 80% yield; mp 277-278° C.; ¹H NMR (DMSO-d₆) δ 1.26 (t, 3H,J=7.0), 4.16 (q, 2H, J=7.0), 6.09 (s, 2H), 7.02 (s, 1H), 7.38 (s, 1H),8.48 (s, 1H).

4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid.4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl ester(45.0 g, 0.172 mol) was added to a solution of KOH (16.8 g, 0.258 mol)in ethanol (500 mL) and the mixture was heated to reflux with stirringfor 20 hours. The reaction flask was then cooled and ethanol wasevaporated under reduced pressure. Then 800 mL of water were added withstirring to fully dissolve the potassium salt, and the solution wasfiltered to remove any impurities. Concentrated HCl was added to bringthe mixture to pH 1, and the free acid was filtered off and dried undervacuum, to give 33.9 g as a beige solid, in 84%; mp >300° C. (lit.²²¹mp >290° C.); ¹H NMR (DMSO-d₆) δ 6.27 (s, 2H), 7.30 (s, 1H), 7.55 (s,1H), 8.72 (s, 1H); ¹³C NMR (DMSO-d₆) δ 98.5, 101.8, 103.8, 107.9, 120.8,137.9, 143.5, 148.1, 153.7, 167.4, 177.4.

6,7-Methylenedioxy-4-quinolone. A suspension of4-hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid (30 g, 0.129mol) in diphenyl ether (320 mL) was heated to reflux with vigorousstirring. The reaction was carefully monitored until it became clear,about 1.5 h, and then immediately removed from heat. By this time all ofthe starting material had dissolved but a black tarry residue remained.The solution was decanted and cooled, allowing the product toprecipitate. This material was filtered and washed with ethyl ether toremove all traces of phenyl ether. A second crop was obtained byvigorously washing the tarry residue with ethanol (16×250 mL), filteringand evaporating the ethanol, and rinsing the material with ethyl ether.The total yield was 14.9 g as a pale yellow solid, in 61%; mp 285-289°C. (lit.²²¹ mp 276° C.); ¹H NMR (DMSO-d₆) δ 5.95 (d, 1H, J=7.3), 6.13(s, 2H), 6.97 (s, 1H), 7.38 (s, 1H), 7.77 (d, 1H, J=7.3); ¹³C NMR(DMSO-d₆) δ 97.5, 102.1, 102.6, 108.7, 119.4, 122.0, 130.8, 138.7,145.8, 151.7.

4-Chloro-6,7-methylenedioxyquinoline. 6,7-Methylenedioxy-4-quinolone(5.0 g, 26.5 mmol) was boiled in POCl₃ (75 mL) for 45 min and thencooled. Excess phosphohoryl chloride was removed under reduced pressureand ice water (100 mL) was added to hydrolyze any residual phosphorylchloride. The mixture was basified (pH 9) with ammonium hydroxide, andthe solid precipitate was filtered. This material was extracted intoethyl ether (8×100 mL), and the ether solution was dried (MgSO₄) andevaporated to provide 4.55 g as a white solid, in 83%; mp 127.5-128° C.(lit. mp 129° C.); ¹H NMR (CDCl₃) δ 6.15 (s, 2H), 7.35 (d, 1H, J=4.7),7.39 (s, 1H), 7.49 (s, 1H), 8.56 (d, 1H, J=4.7); ¹³C NMR (CDCl₃) δ 99.8,102.2, 106.1, 119.9, 123.7, 129.8, 141.2, 147.7, 149.1, 151.4.

Examples 13-16

The representative compounds of the invention at Examples 13-16 wereprepared by deprotection of the corresponding tert-butyldimethylsilylethers (13-15) or the corresponding acetal as described below.

Example 13

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(hydroxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared from the corresponding tert-butyldimethylsilyl ether (Example13.a.) by treatment with AcOH, THF, H₂O (3:1:1) at room temperature;(84% yield); reaction time 48 h; mp 285-286° C.; IR (KBr); 1653, 3448;¹H NMR (DMSO-d₆); δ 3.91 (s, 3H), 4.04 (s, 3H), 4.54 (t, 2H, J=4.4),4.96 (t, 2H, J=4), 6.26 (s, 2H), 7.44 (s, 1H), 7.71 (s, 1H), 7.98 (s,1H), 8.03 (s, 1H), 9.64 (s, 1H); ¹³C NMR (DMSO-d₆); δ 52.6, 56.4, 57.0,59.5, 101.9, 103.0, 104.0, 106.8, 108.8, 111.9, 114.8, 119.1, 128.0,141.2, 144.9, 147.4, 147.7, 150.2, 150.5, 154.6, 163.7; HRMS calcd(M⁺—OH) for C₂₁H₁₇O₅N₂ 377.1137; Found 377.1121.

Example 14

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(2-hydroxyethoxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared from the corresponding tert-butyldimethylsilyl ether (Example14.a.) by treatment by treatment with AcOH, THF, H₂O (3:1:1) at roomtemperature; (76% yield); reaction time 18 h; mp 235° C.; IR (KBr) 1654;¹H NMR (CDCl₃); δ 3.61 (t, 2H, J=5.2), 3.73 (t, 2H, J=5.2), 4.07 (s,3H), 4.14 (s, 3H), 4.22 (t, 2H, J=5.6), 4.71 (t, 2H, J=5.6), 6.2 (s,2H), 7.53 (s, 1H), 7.69 (s, 1H), 7.88 (s, 1H), 8.05 (s, 1H), 9.39 (s,1H). HRMS calcd for C₂₃H₂₂N₂O₇H, 439.1506; found 439.1499.

Example 15

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-N,N-dimethylamino-1-(hydroxymethyl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared from the corresponding tert-butyldimethylsilyl ether (Example15.a.) by treatment with 5N HCl in isopropanol at room temperature for30 min; (57% yield); reaction time 30 min; mp 132° C.; IR (KBr) 1647; ¹HNMR (CDCl₃); δ 2.00 (s, 6H), 2.72-2.81 (m, 1H), 3.16-3.26 (m, 1H), 4.05(s, 3H), 4.12 (s, 3H), 4.20-4.28 (m, 1H), 4.65-4.73 (m, 1H), 4.98 (m,1H), 6.17 (q, 2H, J=1.2), 7.44 (s, 1H), 7.51 (s, 1H), 7.64 (s, 1H), 7.82(s, 1H), 7.82 (s, 1H); 9.33 (s, 1H); ¹³C NMR (CDCl₃) δ: 45.6, 56.2,56.3, 60.0, 64.1, 65.2, 100.9, 101.8, 102.3, 106.6, 108.5, 112.5, 115.0,119.6, 127.5, 141.1, 143.0, 147.1, 147.5, 149.9, 150.0, 154.1, 165.0.

Example 16

8,9-Dimethoxy-2,3-methylenedioxy-5-[2,3-dihydroxy)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one:Prepared from the corresponding acetal (Example 16.a.) by treatment 80%AcOH at reflux for 2 h. The reaction mixture was allowed to cool, andthen concentrated in vacuo. The crude residue was triturated withchloroform (1.5 mL), filtered, and washed with additional chloroform (10mL), to provide 16.5 mg of pure material, in 60% yield; mp 272-274° C.(dec.); IR (KBr) 1631, 3407; ¹H NMR (DMSO-d₆) δ 3.31 (d, 2H, J=8.0),3.95 (s, 3H), 4.07 (s, 3H), 4.63 (m, 3H), 6.33 (s, 2H), 7.55 (s, 1H),7.72 (s, 1H), 8.06 (s, 2H), 8.21 (s, 1H), 9.79 (s, 1H); ¹³C NMR(DMSO-d₆) δ 54.4, 56.5, 57.3, 64.9, 68.8, 103.2, 103.8, 104.6, 108.9,109.0, 112.6, 115.5, 119.3, 127.3, 138.5, 140.6, 148.2, 151.0, 151.3,151.8, 154.8, 163.9; HRMS calcd for C₂₂H₂₀N₂O₇H, 425.1350; found425.1359.

Examples 13.a-16.a

The intermediate iodo compounds of Examples 13.b.-16.b. were cyclizedusing the following general procedure.

A mixture of the requsite 4-amino-6,7-methylenedioxyquinolineo-iodobenzamide derivative (1.0 mmol equiv.), Pd(OAc)₂ (0.2 mmolequiv.), P(o-tolyl)₃ (0.4 mmol equiv.), and Ag₂CO₃ (2.0 mmol equiv) washeated to reflux in DMF (30 mL per mmol equiv.) with stirring. Thereaction mixture was allowed to cool to room temperature, diluted withCHCl₃, and filtered through Celite. The sicciate was extensively washedwith 10% CH₃OH in CHCl₃. The filtrate was concentrated in vacuo and theresidue chromatographed on silica gel using chloroform:methanol.

Example 13.a

Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-(t-butyldimethylsilanyloxy)-ethyl]-2-iodo-4,5-dimethoxybenzamide(36.4% yield); reaction time 30 min; mp 271-273° C.; IR (KBr) 1658; ¹HNMR (CDCl₃) δ 0.00 (s, 6H), 0.68 (s, 9H), 4.04 (s, 3H), 4.12 (s, 3H),4.24 (t, 2H, J=8), 4.65 (t, 2H, J=8), 6.18 (s, 2H), 7.44 (s, 1H), 7.64(s, 1H), 7.85 (s, 1H), 8.01 (s, 1H), 9.29 (s, 1H); HRMS calcd forC₂₇H₃₃ISiN₂O₆H, 637.1153; found 637.1212

Example 14.a

Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(2-(t-butyldimethylsilanyloxy)ethoxy)ethyl]-2-iodo-4,5-dimethoxybenzamide;(75% yield); reaction time 18 h; mp 238° C. (dec.); IR (KBr): 1639; ¹HNMR (CDCl₃); δ 0.00 (s, 6H), 0.85 (s, 9H), 3.54 (t, 2H, J=5.2), 3.70 (t,2H, J=5.2), 4.07 (s, 3H), 4.14 (s, 3H), 4.16 (t, 2H, J=6.0), 4.71 (t,2H, J=6.0), 6.17 (s, 2H), 7.48 (s, 1H) 7.70 (s, 1H), 7.94 (s, 1H), 9.39(s, 1H); HRMS calcd for C₂₃H₂₃N₂O₇H, 439.1505; found 439.1506.

Example 15.a

Prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[1-[(t-butyldimethylsilanyloxy)-methyl]-N-2-dimethylaminoethyl]]-2-iodo-4,5-dimethoxybenzamide(95% yield); reaction time 45 min; ¹H NMR (CDCl₃); 6-0.13 (6H), 069 (s,9H), 1.97 (s, 6H), 1.92 (s, 6H), 2.52 (m, 1H), 2.80 (m, 1H) 3.20 (m,1H), 4.01 (s, 3H), 4.09 (s, 3H), 4.50 (m, 1H), 4.90 (m, 1H), 6.11 (m,2H), 7.30 (s, 1H), 7.61 (s, 1H), 7.79 (s, 1H), 8.19 (s, 1H), 9.32 (s,1H).

Example 16.a

8,9-Dimethoxy-2,3-methylenedioxy-5-[2,2-dimethyl[1,3]dioxolan-4-yl]methyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-onewas prepared fromN-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2,3-dihydroxy)propyl]-2-iodo-5,6-dimethoxybenzamide(22% yield); reaction time 45 min); mp 241-244° C. (dec.); IR(CHCl₃)1652; ¹H NMR (CDCl₃) δ 1.34 (s, 3H), 1.36 (s, 3H), 3.95 (m, 2H), 4.08(s, 3H), 4.14 (s, 3H), 4.35 (m, 1H), 4.55 (m, 1H), 4.77 (m, 1H), 6.19(s, 2H), 7.48 (s, 1H), 7.70 (s, 1H), 7.87 (s, 2H), 8.05 (s, 1H), 9.40(s, 1H); ¹³C NMR (CDCl₃) δ 25.5, 26.5, 54.0, 56.3, 56.4, 69.4, 75.5,101.6, 102.1, 102.3, 107.0, 108.7, 109.7, 111.8, 114.9, 119.1, 127.8,141.1, 143.5, 147.4, 147.7, 150.1, 150.4, 154.4, 164.6; HRMS calcd forC₂₅H₂₄N₂O₇H 465.1662; found 435.1677. The compound8,9-Dimethoxy-2,3-methylenedioxy-5-[2,2-dimethyl[1,3]dioxolan-4-yl]methyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-oneis also a compound of the invention.

Examples 13.b.-16.b.

The intermediate 4-amino-6,7-methylenedioxyquinoline o-iodobenzamidederivatives used in Examples 13.a.-16.a. were prepared using thefollowing general procedure.

A 2.0M solution of oxalyl chloride in CH₂Cl₂ (1.3 equiv.) was added to asolution of 2-iodo-5,6-dimethoxybenzoic acid (1.0 equiv.) in anhydrousCH₂Cl₂ (≈60 mL per 10 mmol benzoic acid) and the solution stirred atreflux for 3 h. The mixture was allowed to cool and was thenconcentrated to dryness in vacuo. To the residue was added a solution ofappropriate 4-amino-6,7-dimethoxyquinoline (1.0 equiv), triethylamine (2equiv.) in CH₂Cl₂ (≈60 mL per 4 mmol aminoquinoline). The reactionmixture was then stirred at reflux under N₂. In the case of thosederivatives that have an alkylamine incorporated in their structure, theresidue was partitioned between CHCl₃ and 10% NaOH. The aqueous layerwas repeatedly separated with CHCl₃. All of the CHCl₃ solutions (initialpartition and extracts) were combined and dried (MgSO₄). The aqueouslayer was neutralized with 20% NaOH and extracted with CHCl₃, dried(MgSO₄) and evaporated.

Example 13.b

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-(t-butyldimethylsilanyloxy)-ethyl]-2-iodo-4,5-dimethoxybenzamide.Prepared from4-[N-[2-(t-Butyldimethylsilanyloxy)]ethyl]amino-6,7-methylenedioxyquinoline(400 mg, 1.15 mmol) in 51.7% yield with a reaction time of 12 h, fromthe acid chloride prepared using 5.0 mmol of oxalyl chloride and 1.38mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 8h had: mp 79-80° C.;IR (KBr); 1653 ¹H NMR (CDCl₃); δ 0.004 (d, 3H, J=4.2 Hz), 0.82 (s, 9H),3.26 (s, 3H), 3.67 (s, 3H), 3.84-4.02 (m, 4H), 6.13 (d, 2H, J=4 Hz),6.40 (s, 1H), 7.02 (s, 1H), 7.33 (d, 1H, J=4.2 Hz), 7.36 (s, 1H), 7.42(s, 1H), 8.52 (d, 1H, J=4 Hz); HRMS calcd for C₂₇H₃₃ISiN₂O₆H 637.1232;observed 637.1212

Example 14.b

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(2-(t-butyldimethylsilanyloxy)ethoxy)ethyl]-2-iodo-4,5-dimethoxybenzamide.Prepared from4-[N-[2-[2-(t-Butyldimethylsilanyloxy)ethoxy]ethyl]ethyl]amino-6,7-methylenedioxyquinoline(354 mg, 9.0 mmol) in 60% yield with a reaction time of 24 h, from theacid chloride prepared using 4.5 mmol of oxalyl chloride and 1.8 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 81 had: ¹H NMR (CDCl₃); δ0.006 (s, 6H), 0.83 (s, 9H), 3.27 (s, 3H), 3.48 (t, 2H, J=4.6), 3.67 (t,2H, J=5.6), 3.69 (s, 3H), 3.76-4.55 (m, 4H), 6.10 (s, 2H), 6.36 (s, 1H),6.99 (s, 1H), 7.30-7.32 (three singlets, 3H), 8.52 (d, 1H, J=4.8).

Example 15.b

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[1-[(t-butyldimethylsilanyloxy)-methyl]-N-2-dimethylaminoethyl]]-2-iodo-4,5-dimethoxybenzamide.Prepared from4-[N-4-[2-(N,N-dimethylamino)-1-[(t-butyldimethylsilanyloxy)methyl]-ethyl]amino-6,7-methylenedioxyquinoline(0.48 mg, 1.2 mol) in 55% yield with a reaction time of 18 h, from theacid chloride prepared using 5.9 mmol of oxalyl chloride and 2.4 mmol of2-iodo-5,6-dimethoxybenzoic acid. Compound 8j had: IR(CHCl₃) 1656; ¹HNMR (CDCl₃) [unresolved atropisomers in a an apparent 57:43 ratio arr.t.] major atropisomer δ 0.01 (s, 6H), 0.84 (s, 9H), 2.34 (s, 6H), 2.55(m, 1H), 2.85 (m, 1H); 3.43 (s, 3H), 3.71 (s, 3H) 3.86-4.04 (m, 3H),6.12 (s, 2H), 6.56 (s, 1H), 7.29-7.31 (s, 1H), 7.67 (d, 1H, J=5.0), 8.00(s, 1H), 8.59 (d, 1H, J=4.4); minor atropisomer δ 0.17 (s, 6H), 0.96 (s,9H), 2.15 (s, 6H), 2.55 (m, 1H), 2.85 (m, 1H), 3.36 (s, 3H), 3.72 (s,3H) 3.86-4.04 (m, 3H), 6.13 (s, 2H), 6.53 (s, 1H), 7.00 (s, 1H), 7.31(s, 1H), 7.51 (d, 1H, J=4.8), 8.25 (s, 1H), 8.55 (d, 1H, J=5.2).

Example 16.b

N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2,3-dihydroxy)propyl]-2-iodo-5,6-dimethoxybenzamide.Prepared from4-[N-(2,2-dimethyl-[1,3]dioxolan-4-yl)methyl]amino-6,7-methylenedioxyquinoline(290 mg, 0.9 mmol) in 47% yield with a reaction time of 12 h, from theacid chloride prepared using 30 mmol of oxalyl chloride and 13 mmol of2-iodo-5,6-dimethoxybenzoic acid. The acid chloride was added as amethylene chloride solution to a solution of 7k in 125 mL of DMEcontaining triethylamine (3.04 g 30.1 mmol). Compound 8k had: IR(CHCl₃)1653; ¹H NMR (CDCl₃) δ 1.21 (s, 3H), 1.33 (s, 3H), 3.33 (s, 3H), 3.76(s, 3H), 3.94 (m, 3H), 4.61 (m, 2H), 6.18 (s, 1H), 6.39 (s, 1H), 7.05(s, 1H), 7.31 (d, 1H, J=4.8), 7.46 (s, 1H), 7.49 (s, 1H), 8.61 (d, 1H,J=4.8); ¹³C NMR (CDCl₃) δ 25.6, 26.9, 55.6, 56.1, 56.4, 68.2, 73.2,82.8, 98.2, 98.7, 102.4, 106.1, 110.3, 120.7, 121.7, 124.1, 133.3,147.5, 148.0, 148.8, 149.5, 150.0, 151.5, 152.3, 167.8; HRMS calcd forC₂₅H₂₅N₂O₇₁H, 593.0785; found 593.0802.

Examples 13.c.-15.c

The intermediate alcohols from Examples 13.d.-15.d. were converted totheir corresponding silyl ethers using the following general procedure.

A mixture of the 4-amino-6,7-methylenedioxyquinoline derivative (1.0mmole equiv.), imidazole (1.1 mmol equiv.) and t-butyldimethylsilylchloride (1.2 mmol equiv.) in DMF (15 mL per mmol equiv) was stirred atroom temperature for 6 h. DMF was removed in vacuo, water was added toresidue, and solid was filtered and dried.

Example 13.c

4-[N-[2-(t-Butyldimethylsilanyloxy)]ethyl]amino-6,7-methylenedioxyquinoline.Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)ethanolamine in 48.7%yield; mp 215-216° C.; ¹H NMR (DMSO-d₆) δ 0.01 (s, 6H), 0.85 (s, 9H),3.39 (dd, 2H, J=6, 12), 3.80 (t, 2H, J=6.2), 6.14 (s, 2H), 6.42 (d, 1H,J=5.4), 7.12 (s, 1H), 7.60 (s, 1H), 8.18 (d, 1H, J=4.8).

Example 14.c

4-[N-[2-[2-(t-Butyldimethylsilanyloxy)ethoxy]ethyl]ethyl]amino-6,7-methylenedioxyquinoline.Prepared from2-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethoxyethanol in 39%yield (overall yield from 5); ¹H NMR (CDCl₃) δ 0.1 (s, 6H), 0.92 (s,9H), 3.64-3.69 (m, 4H), 3.84 (d, 2H, J=5.2,), 3.93 (d, 2H, J=5.2), 6.15(s, 2H), 6.56 (d, 1H, J=6.4), 7.42 (s, 1H), 7.82 (s, 1H), 8.18 (d, 1H,J=6.4).

Example 15.c

4-[N-4-[2-(N,N-dimethylamino)-1-[(t-butyldimethylsilanyloxy)methyl]-ethyl]amino-6,7-methylenedioxyquinoline.Prepared from2-[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]-3-(N,N-dimethylamino)propanolin 25% yield (overall yield from 5); ¹H NMR (CDCl₃) [unresolvedatropisomers in a an apparent 57:43 ratio at r.t.] major atropisomer δ0.07 (s, 6H), 0.92-0.94 (s, 9H), 2.24 (s, 6H), 2.45-2.55 (m, 2H),3.60-4.05 (m, 3H), 5.40 (d, 1H), 6.09 (s, 2H), 6.45 (d, 1H, J=6.4), 7.02(s, 1H), 7.30 (s, 1H), 8.18 (d, 1H, J=6.4); minor atropisomer δ 0.09 (s,6H), 0.94 (s, 9H), 2.30 (s, 6H), 2.45-2.55 (m, 2H), 3.60-4.05 (m, 3H),5.40 (d, 1H), 6.0 (s, 2H), 6.45 (d, 1H, J=6.4), 7.02 (s, 1H), 7.30 (s,1H), 8.18 (d, 1H, J=6.4)

Example 16.c

4-[N-(2,2-dimethyl-[1,3]dioxolan-4-yl)methyl]amino-6,7-methylenedioxyquinoline.A mixture of3-[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]-1,2-propandiol (500 mg,1.9 mmol), p-toluenesulfonic acid (5 mg, 0.02 mg) in DMF (20 mL) and2,2-dimethoxypropane (5 mL), was heated to 80° C. and stirred at thistemperature for 18 h. To the cooled solution was added 1 mL of pyridineand the solvent evaporated in vacuo. The crude material waschromatographed in 96:4 chloroform-methanol to give 466 mg of theacetonide, in 81% yield; mp 219-221° C.; ¹H NMR (CD₃OD) δ 1.35 (s, 3H),1.38 (s, 3H), 3.74 (m, 3H), 4.19 (m, 1H), 4.49 (m, 1H), 6.28 (s, 2H),6.94 (d, 1H, J=7.2), 7.20 (s, 1H), 7.74 (s, 1H), 8.24 (d, 1H, J=7.2);¹³C NMR (CD₃OD) δ 23.5, 25.1, 45.0, 66.0, 73.6, 96.5, 97.7, 97.8, 103.1,109.1, 112.2, 135.8, 138.6, 148.4, 153.3, 155.3; HRMS calcd forC₁₆H₁₈N₂O₄: 302.1267; found 302.1267.

Examples 13.d-16.d

The intermediate 4-amino-6,7-dimethoxyquinoline derivatives used inExamples 13.c-16.c. were prepared using the following general procedure.

4-Chloro-6,7-methylenedioxyquinoline was stirred in refluxing phenol(5.5 mol equiv.) for 2.5 h. The temperature was lowered to 100° C. andthe primary amine (1.0 mol equiv.) added with stirring. The reaction wasthen allowed to stir at 100° C. for several hours, and the phenolremoved by Kugelrohr distillation under reduced pressure. In the case ofthose derivatives that have an alkylamine incorporated in theirstructure, the residue was partitioned between CHCl₃ and 10% NaOH. Theaqueous layer was repeatedly separated with CHCl₃. All of the CHCl₃solutions (initial partition and extracts) were combined and dried(MgSO₄). Other 4-amino-6,7-methylenedioxyquinoline derivatives werepurified by column chromatography.

Example 13.d

N-(6,7-Methylenedioxyquinolin-4-yl)ethanolamine was prepared fromethanolamine (0.6 g, 10 mmol) from in 53.9% yield with a reaction timeof 24 h: mp 233-234° C.; ¹H NMR (DMSO-d₆); δ 3.51 (dd, 2H, J=10.4, 6.),3.69 (t, 2H, J=6.0), 6.27 (s, 2H), 6.72 (d, 1H, J=7.0), 7.37 (s, 1H),8.12 (s, 1H), 8.29 (d, 1H, J=7.0); ¹³C NMR (DMSO-d₆); 46.5, 59.5, 98.6,98.8, 100.3, 103.8, 113.2, 137.6, 141.0, 148.2, 152.8, 155.0; HRMS calcdfor C₁₂H₁₂N₂O₃H, 232.0848; found 232.0881.

Example 14.d

2-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethoxyethanol wasprepared from 2-[2-(hydroxyethyl)ethoxy]ethylamine (0.76 g, 7.2 mmol)with a reaction time of 18 h. The compound was converted directly to itst-butyldimethylsilanyloxy derivative in Example 14.c. above.

Example 15.d

2-[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]-3-(N,N-dimethylamino)propanolwas prepared from 1-(hydroxymethyl)-2-(N,N-dimethylethylenediamine (1.13g, 9.6 mmol) with a reaction time of 48 h. The compound was converteddirectly to its t-butyldimethylsilanyloxy derivative in Example 15.c.above.

Example 16.d

3-[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]-1,2-propandiol wasprepared from 3-amino-1,2-propanediol (1.32 g, 14.5 mmol) in 34% yieldwith a reaction time of 24 h: mp 213-217° C. (dec.); ¹H NMR (CD₃OD) δ3.67 (m, 5H), 6.26 (s, 2H), 6.87 (d, 11H, J=7.2), 7.19 (s, 1H), 7.71 (s,1H), 8.21 (d, 1H, J=7.2); ¹³C NMR (CD₃OD) δ 45.7, 63.1, 69.4, 96.8,97.4, 97.8, 103.0, 112.3, 136.1, 138.9, 148.2, 153.0, 155.0; HRMS calcdfor C₉H₇N₃O₂: 262.0954; found 262.0954.

Example 17

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine(4a): To a solution of8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one(160 mg, 0.38 mmol) in THF (650 mL) was added LiAlH₄ (75 mg, 2.0 mmol),and the mixture was stirred under nitrogen at reflux. After 2 h, anadditional 2.0 mmol of LiAlH₄ was again added. The reaction was refluxedfor an additional 3 h, then allowed to cool to room temperature. Thereaction was quenched by the sequential addition of water (5 drops), 10%NaOH (5 drops), and water (5 drops). The mixture was filtered throughCelite and evaporated, and the crude mixture was chromatographed onsilica in 98:2 chloroform-methanol, to give 132 mg of the reducedproduct, in 85% yield; mp 271-273° C. (dec.); ¹H NMR (CDCl₃) δ 2.24 (s,6H), 2.58 (t, 2H, J=6.8), 3.12 (t, 2H, J=6.8), 3.97 (s, 3H), 4.02 (s,3H), 4.27 (s, 2H), 6.13 (s, 2H), 6.79 (s, 1H), 7.38 (s, 2H), 7.61 (s,1H), 9.05 (s, 1H); ¹³C NMR (CDCl₃) δ 46.0, 50.6, 51.2, 56.2, 26.3, 58.4,99.6, 101.7, 105.7, 106.6, 110.0, 120.7, 123.1, 124.8, 131.1, 144.1,146.9, 148.0, 149.0, 149.4, 149.8, 150.2; HRMS calcd for C₂₃H₂₅N₃O₄:407.1845; found 407.1848.

Example 18

8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine.The title compound was prepared as follows.8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one(80 mg, 0.18 mmol; Example 7) in THF (150 mL) was added to LiAlH₄ (50mg, 1.3 mmol), and the mixture was stirred under nitrogen at reflux for4 h. The reaction was quenched by the sequential addition of water (5drops), 10% NaOH (5 drops), and water (5 drops). The mixture wasfiltered through Celite and evaporated, and the crude mixture waschromatographed on silica in 1.0% methanol in chloroform to give 35 mgof the reduced product, in 45.4% yield; mp 153-154° C.; ¹H NMR (CDCl₃) δ1.16 (d, 3H, J=8), 2.38 (dd, 2H, J=12.2, 8.0), 3.68-3.80 (m, 1), 3.88(s, 3H), 4.24 (s, 2H), 6.16 (s, 2H), 6.64 (s, 1H), 7.24 (s, 1H), 7.40(s, 2H), 7.62 (s, 1H), 8.88 (s, 1H); ¹³C NMR (CDCl₃) δ: 17.7, 45.6,46.0, 56.2, 56.4, 57.8, 64.2, 100.1, 101.7, 105.8, 106.4, 108.5, 120.5,120.6, 123.6, 126.9, 143.4, 146.6, 147.7, 148.9, 149.5, 149.6, 150.0;HRMS calcd for C₂₄H₂₇N₃O₄H 422.2002; found 422.2081.

Example 198,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]-1,6-naphthyridin-6-one

A mixture ofN-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-diethylamino)ethyl]-2-iodo-4,5-dimethoxybenzamide(577 mg, 1.0 mmol), Pd(OAc)₂ (45, 0.2 mmol), P(o-tolyl)₃ (122 mg, 0.4mmol), and silver carbonate (550 mg, 2.0 mmol) was heated to reflux inDMF (30 mL) and stirred under nitrogen for 30 minutes. The reactionmixture was cooled to room temperature, diluted with chloroform andfiltered though a bed of Celite. The filter was washed well with 90:10chloroform-methanol. Then the solvent was removed under reduced pressureand the resulting residue was chromatographed on silica gel using 99:1chloroform-methanol to give the cyclized compound (250 mg) as a whitesolid, in 56% yield; mp 221-223° C. (dec.); IR(CHCl₃) 3029, 3009, 2971,2939, 2910, 1648, 1611, 1570, 1523, 1497, 1467, 1386, 1310, 1267, 1248,1217, 1213, 1166, 1040; ¹H NMR (CDCl₃) δ 0.95 (t, 6H, J=7.0), 2.80 (1,4H, J=7.0), 3.04 (t, 2H, J=6.7), 4.06 (s, 3H), 4.13 (s, 3H), 4.63 (t,2H, J=6.7), 6.17 (s, 2H), 7.46 (s, 1H), 7.68 (s, 1H), 7.90 (s, 1H), 7.96(s, 1H), 9.37 (s, 1H); ¹³C NMR (CDCl₃) δ 12.0, 47.6, 49.6, 51.7, 56.3,101.4, 102.0, 102.2, 107.0, 108.9, 111.8, 115.0, 119.5, 127.7, 141.1,143.5, 147.3, 147.7, 149.9, 150.3, 154.2, 164.2; HRMS calcd forC₂₅H₂₇O₅N₃H, 450.2030; found: 450.2032.

a. 4-[[2-(Diethylamino)ethyl]amino]-6,7-methylenedioxyquinoline.4-Chloro-6,7-methylenedioxyquinoline. (1.0 g, 4.83 mmol) was stirred inboiling phenol for 2.5 hours. Then the mixture was cooled to 140° C. andN,N-diethylethylenediamine (1.16 g, 10.0 mmol) was added. The reactionmixture was stirred at this temperature for 18 hours, and then phenolwas removed on the Kugelrohr. The crude residue was partitioned betweendilute HCl (100 mL) and chloroform (100 mL), and the organic phase wasextracted with dilute HCl (100 mL). The combined aqueous phases werewashed with chloroform (100 mL) and then basified with 30% NaOH,extracted into chloroform (3×100 mL), dried (MgSO₄) and evaporated togive 793 mg as a white solid, in 58% yield; mp 201-202° C.; IR(CHCl₃)3364, 2967, 2936, 2907, 2875, 1620, 1546, 1466, 1295, 1222, 1218, 1210,1152, 1041; ¹H NMR (CDCl₃) δ 1.09 (t, 6H, J=7.2), 2.61 (q, 4H, J=7.2),2.82 (t, 2H, J=5.8), 3.26 (m, 2H), 5.71 (br, 1H), 6.08 (d, 2H), 6.35 (d,1H, J=5.2), 7.03 (s, 1H), 7.31 (s, 1H), 8.40 (d, 1H, J=5.2); ¹³C NMR(CDCl₃) δ 12.2, 40.1, 46.7, 51.0, 96.1, 99.0, 101.5, 106.7, 114.5,146.5, 146.7, 149.1, 149.6, 149.9; HRMS calcd for C₁₆H₂₁O₂N₃: 287.1634;found: 287.1631.

b.N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-diethylamino)ethyl]-2-iodo-4,5-dimethoxybenzamide.Oxalyl chloride (1.12 g, 8.8 mmol) was added to a solution of2-Iodo-4,5-dimethoxybenzoic acid (820 mg, 2.6 mmol; see above) inanhydrous methylene chloride (40 mL) and the stirred mixture wasrefluxed for 4 hours. The mixture was then concentrated to dryness underreduced pressure. The acid chloride was dissolved in 40 mL of methylenechloride and added to a solution of4-[[2-(Diethylamino)ethyl]amino]-6,7-methylenedioxyquinoline (640 mg,2.2 mmol), and triethylamine (2.2 g, 22 mmol) in methylene chloride (50mL) and the resulting mixture was stirred at reflux under nitrogen for 2hours. The reaction mix was cooled and washed with a saturated solutionof sodium bicarbonate (3×75 mL), and extracted into dilute HCl (4×100mL). The aqueous extract was then neutralized with 30% NaOH andextracted with CHCl₃ (4×100 mL), washed with brine (100 mL), dried(MgSO₄) and evaporated, yielding 1.1 g as a sticky semisolid glue, in86% yield; ¹H NMR (CDCl₃) δ 0.96 (t, 6H, J=7.2), 2.54 (q, 4H, J=7.2),2.82 (m, 2H), 3.29 (s, 3H), 3.71 (s, 3H), 3.92 (m, 1H), 4.46 (m, 1H),6.12 (s, 2H), 6.37 (s, 1H), 7.00 (s, 1H), 7.27 (d, 1H, J=4.8), 7.33 (s,1H), 7.39 (s, 1H), 8.52 (d, 1H, J=4.8); ¹³C NMR (CDCl₃) δ 11.8, 47.1,47.5, 50.7, 55.5, 56.1, 82.7, 98.5, 102.2, 106.7, 110.6, 120.1, 121.8,122.7, 133.7, 146.3, 148.1, 148.3, 148.5, 149.0, 149.7, 151.0, 170.0;HRMS calcd for C₂₅H₂₈O₅N₃1H, 578.1153; found: 578.1153.

The intermediate 4-Chloro-6,7-methylenedioxyquinoline was prepared asdescribed above.

The intermediate 2-Iodo-4,5-dimethoxybenzoic acid was prepared asfollows.

c. 2-Iodo-4,5-dimethoxybenzoic acid. A mixture of2-amino-4,5-dimethoxybenzoic acid (10.0 g, 50 mmol) in water (100 mL)and concentrated H₂SO₄ (14 mL) was cooled to 5° C. and a solution ofNaNO₂ (3.5 g) in water (12.5 mL) was added in a dropwise fashion whilemaintaining the temperature between 0-5° C. Following the addition themixture was stirred at this temperature for an additional 30 minutes.Then a solution of KI (13.0 g, 78.3 mmol) in water (20.5 mL) andconcentrated H₂SO₄ (4.4 mL) was rapidly added and the flask wastransferred to an oil bath that had been preheated to 105° C. Themixture was stirred for 30 minutes following the onset of reflux. Theflask was then cooled and extracted into chloroform (3×300 mL), washedwith water (3×200 mL), dilute HCl (200 mL), and brine (200 mL), then thesolvent was dried (Na₂SO₄) and evaporated, and the residue waschromatographed in chloroform to give 13.1 g as a white solid, in 84%yield; mp 162.0-163.5° C. (lit. mp 159-160° C.); ¹H NMR (CDCl₃) δ 3.93(s, 3H), 3.95 (s, 3H), 7.46 (s, 1H), 7.65 (s, 1H); ¹³C NMR (CDCl₃)δ56.1, 56.4, 85.8, 114.8, 124.3, 124.5, 148.8, 152.7, 170.5.

Example 20

Using procedures similar to those described above, the compound2,3-dimethoxy-8,9-methylenedioxy-11-[2-(4-methylpiperazin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-onewas also prepared.

Example 21

Using procedures similar to those described above, the followingcompounds of the invention were also prepared:8,9-dimethoxy-2,3-methylenedioxy-5-(2-piperidinoethyl)-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-[2-(4-benzylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-formylmethyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;and8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.

Example 22

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet ‘Compound X’ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodiumhydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injectionq.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml ‘Compound X’ (free acidform) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1Polyethylene glycol 400 200.0 01 N Sodium hydroxide solution q.s. (pHadjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Injection 3(1 mg/ml) mg/ml ‘Compound X’ (free base form) 1.0 Citric Acid 0.1% D5Wq.s. ad 1 mL (vii) Aerosol mg/can ‘Compound X’ 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound selected from the group consisting of11,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-11-[2-(dimethylamino)ethyl]-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-diethylamino)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)-1-methylethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-(2-tetrahydrofuranyl)methyl-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(pyrrolidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(piperidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(pyrrolidin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(4-methylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[3-(N,N-dimethylamino)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-(2-tetrahydrofuranyl)methyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(hydroxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(2-hydroxyethoxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-N,N-dimethylamino-1-(hydroxymethyl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2,3-dihydroxy)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;2,3-dimethoxy-8,9-methylenedioxy-11-[2-(4-methylpiperazin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-dimethoxy-2,3-methylenedioxy-5-(2-piperidinoethyl)-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-[2-(4-benzylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-formylmethyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;and8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one,or a pharmaceutically acceptable salt thereof.
 2. A compound accordingto claim 1 in the form of a pharmaceutically acceptable salt, whereinthe pharmaceutically acceptable salt is an organic acid addition saltselected from the group consisting of tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate and α-glycerophosphate.
 3. A compound according to claim1 in the form of a pharmaceutically acceptable salt, wherein thepharmaceutically acceptable salt is an inorganic acid addition saltselected from the group consisting of chloride, sulfate, nitrate,bicarbonate and carbonate.
 4. A compound according to claim 1 in theform of a pharmaceutically acceptable salt, wherein the pharmaceuticallyacceptable salt is an inorganic base addition salt selected from thegroup consisting of sodium, potassium, lithium and calcium.
 5. Acompound according to claim 2, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.6. A compound according to claim 2, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.7. A compound according to claim 2, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.8. A compound according to claim 3, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.9. A compound according to claim 3, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.10. A compound according to claim 3, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.11. A pharmaceutical composition comprising a compound selected from thegroup consisting of:11,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-11-[2-(dimethylamino)ethyl]-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-diethylamino)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)-1-methylethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-(2-tetrahydrofuranyl)methyl-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(pyrrolidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(piperidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(pyrrolidin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(4-methylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[3-(N,N-dimethylamino)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-(2-tetrahydrofuranyl)methyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(hydroxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(2-hydroxyethoxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-N,N-dimethylamino-1-(hydroxymethyl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2,3-dihydroxy)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;2,3-dimethoxy-8,9-methylenedioxy-11-[2-(4-methylpiperazin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-dimethoxy-2,3-methylenedioxy-5-(2-piperidinoethyl)-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-[2-(4-benzylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]-1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-formylmethyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;and8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one,or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition according to claim11, wherein the compound is in the form of a pharmaceutically acceptablesalt, wherein the pharmaceutically acceptable salt is an organic acidaddition salt selected from the group consisting of tosylate,methanesulfonate, acetate, citrate, malonate, tartarate, succinate,benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate.
 13. Apharmaceutical composition according to claim 11, wherein the compoundis in the form of a pharmaceutically acceptable salt, wherein thepharmaceutically acceptable salt is an inorganic acid addition saltselected from the group consisting of chloride, sulfate, nitrate,bicarbonate and carbonate.
 14. A pharmaceutical composition according toclaim 11, wherein the compound is in the form of a pharmaceuticallyacceptable salt, wherein the pharmaceutically acceptable salt is aninorganic base addition salt selected from the group consisting ofsodium, potassium, lithium and calcium.
 15. A pharmaceutical compositionaccording to claim 12, wherein the compound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.16. A pharmaceutical composition according to claim 12, wherein thecompound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.17. A pharmaceutical composition according to claim 12, wherein thecompound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.18. A pharmaceutical composition according to claim 13, wherein thecompound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.19. A pharmaceutical composition according to claim 13, wherein thecompound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.20. A pharmaceutical composition according to claim 13, wherein thecompound is8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one.21. A pharmaceutical composition according to claim 11 in oral dosageform.
 22. A pharmaceutical composition according to claim 11 inparenteral dosage form.
 23. A method of inhibiting breast cancer cellgrowth comprising administering to a mammal a compound selected from thegroup consisting of:11,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-11-[2-(dimethylamino)ethyl]-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-diethylamino)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)-1-methylethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dmethoxy-8,9-methylenedioxy-11-(2-tetrahydrofuranyl)methyl-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(pyrrolidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;2,3-Dimethoxy-8,9-methylenedioxy-11-[2-(piperidin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(pyrrolidin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(4-methylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[3-(N,N-dimethylamino)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-(2-tetrahydrofuranyl)methyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(hydroxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(2-hydroxyethoxy)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-N,N-dimethylamino-1-(hydroxymethyl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2,3-dihydroxy)propyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-1-methylethyl]-5,6-dihydro-dibenzo[c,h]1,6-naphthyridine;8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;2,3-dimethoxy-8,9-methylenedioxy-11-[2-(4-methylpiperazin-1-yl)ethyl]-11H-5,6,11-triazachrysen-12-one;8,9-dimethoxy-2,3-methylenedioxy-5-(2-piperidinoethyl)-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-[2-(4-benzylpiperazin-1-yl)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one;8,9-dimethoxy-2,3-methylenedioxy-5-formylmethyl-5H-dibenzo[c,h]1,6-naphthyridin-6-one;and8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one,or a pharmaceutically acceptable salt thereof.